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{{#unlinkedwikibase:id=Q5037837}}{{Short description|Antibiotic-resistant bacteria}}
{{Infobox medical condition
| name =
| synonym =CRE infection<ref>{{Cite web |title=Carbapenem-resistant Enterobacteriaceae (CRE) |url=https://stacks.cdc.gov/view/cdc/83751 |url-status=live |archive-url=https://web.archive.org/web/20240908004634/https://stacks.cdc.gov/view/cdc/83751 |archive-date=8 September 2024 |access-date=3 September 2024 |website=stacks.cdc.gov}}</ref>
| image = {{Photomontage
| photo1a =Klebsiella pneumonia Bacterium (13383560994).jpg
| photo2a =CRE infection.webp
| size = 350
| spacing = 3
| color = #FFFFFF
| border = 0
| color_border =
}}
| image_size =
| image_thumbtime =
| alt =
| caption = *{{align|left|Top:Scanning electron micrograph showing Carbapenem-resistant ''Klebsiella pneumoniae'' interacting with a human neutrophil }}
* {{align|left|Bottom:Classification of different mechanisms of drug resistance in CRE<ref name=su/>}}
|specialty = Infectious disease
|symptoms = Cough,fever,shortness of breath, nausea<ref name=ref/>
|complications =
|onset =
|duration =
|types =
|causes =
|risks = High and sometimes excessive use of antibiotics<ref name=cd/>
|diagnosis = E-test, or automated susceptibility testing<ref name=cd/>
|differential =Methicillin-resistant Staphylococcus aureus, Vancomycin-resistant Enterococci, Extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae<ref>{{Cite web |title=Facility Guidance for Control of Carbapenem-resistant Enterobacteriaceae |url=https://www.cdc.gov/infection-control/media/pdfs/Guidelines-CRE-Guidance-508.pdf |url-status=live |archive-url=https://web.archive.org/web/20240817012522/https://www.cdc.gov/infection-control/media/pdfs/Guidelines-CRE-Guidance-508.pdf |archive-date=17 August 2024 |access-date=6 September 2024 |website=CDC}}</ref>{{additional citation needed}}
|treatment=Trimethoprim/sulfamethoxazole, nitrofurantoin(though there are several other medications/depends on infection site)<ref name=ref/>
|frequency=KPC is endemic in the United States, Mexico, Portugal, Italy, Israel, and Greece<ref name=ref/>
}}

'''Carbapenem-resistant Enterobacteriaceae''' ('''CRE''') (or '''carbapenemase-producing Enterobacteriaceae''') are [[Gram-negative bacteria]] that are resistant to the [[carbapenem]] class of [[antibiotics]], considered the [[drug of last resort|drugs of last resort]] for such infections. They are resistant because they produce an [[enzyme]] called a [[carbapenemase]] that disables the drug molecule. The resistance can vary from moderate to severe. [[Enterobacteriaceae]] are common [[Commensalism|commensals]] and infectious agents. Experts fear CRE as the new "[[super bug (bacteria)|superbug]]".<ref name=USAtoday/> The bacteria can kill up to half of patients who get [[Sepsis|bloodstream infections]].<ref name="CDC03513">{{Cite press release |title=CDC: Action needed now to halt spread of deadly bacteria: Data show more inpatients suffering infections from bacteria resistant to all or nearly all antibiotics |date=March 5, 2013 |publisher=The Centers for Disease Control |url=https://www.cdc.gov/media/releases/2013/p0305_deadly_bacteria.html |quote=During just the first half of 2012, almost 200 hospitals and long-term acute-care facilities treated at least one patient infected with these bacteria. |access-date=March 5, 2013 |url-status=live |archive-url=https://web.archive.org/web/20171220135429/https://www.cdc.gov/media/releases/2013/p0305_deadly_bacteria.html |archive-date=December 20, 2017}}</ref> [[Tom Frieden]], former head of the [[Centers for Disease Control and Prevention]] has referred to CRE as "nightmare bacteria".<ref name=CDC03513/><ref>{{Cite web |last=Breslow |first=Jason |date=8 Jan 2014 |title=Illinois "Nightmare Bacteria" Outbreak Raises Alarms |url=https://www.pbs.org/wgbh/pages/frontline/health-science-technology/hunting-the-nightmare-bacteria/illinois-nightmare-bacteria-outbreak-raises-alarms/ |url-status=live |archive-url=https://web.archive.org/web/20140328191050/http://www.pbs.org/wgbh/pages/frontline/health-science-technology/hunting-the-nightmare-bacteria/illinois-nightmare-bacteria-outbreak-raises-alarms/ |archive-date=28 March 2014 |access-date=24 Apr 2014 |website=PBS.org}}</ref> Examples of enzymes found in certain types of CRE are KPC (''Klebsiella pneumoniae'' carbapenemase) and NDM (New Delhi Metallo-beta-lactamase). KPC and NDM are enzymes that break down carbapenems and make them ineffective. Both of these enzymes, as well as the enzyme VIM (Verona Integron-Mediated Metallo-β-lactamase) have also been reported in ''[[Pseudomonas]]''.<ref name="CDC 2021">{{Cite web |date=February 2021 |title=Pseudomonas aeruginosa - HAI |url=https://www.cdc.gov/hai/outbreaks/pseudomonas-aeruginosa.html |url-status=live |archive-url=https://web.archive.org/web/20220413144346/https://www.cdc.gov/hai/outbreaks/pseudomonas-aeruginosa.html |archive-date=13 April 2022 |access-date=13 April 2022 |website=CDC}}</ref>

==Symptoms and signs==
[[File:SymptomsFeverCoughSOB (cropped).jpg|thumb|450px|left| Individual with shortness of breath]]
In terms of the presentation, we find that location determines the symptoms; in pneumonia(lungs) you would find:<ref name="cd">{{Cite web |date=14 May 2024 |title=About Carbapenem-resistant Enterobacterales |url=https://www.cdc.gov/cre/about/index.html |url-status=live |archive-url=https://web.archive.org/web/20240810075942/https://www.cdc.gov/cre/about/index.html |archive-date=10 August 2024 |access-date=2 September 2024 |website=Enterobacterales (carbapenem-resistance) |language=en-us}}</ref><ref name="ref">{{Cite book |last=Sattar |first=Saud Bin Abdul |url=https://www.ncbi.nlm.nih.gov/books/NBK513321/ |title=StatPearls |last2=Nguyen |first2=Andrew D. |last3=Sharma |first3=Sandeep |date=2024 |publisher=StatPearls Publishing |chapter=Bacterial Pneumonia |access-date=2024-09-02 |archive-url=https://web.archive.org/web/20201101083228/https://www.ncbi.nlm.nih.gov/books/NBK513321/ |archive-date=2020-11-01 |url-status=live}}</ref>
* [[Cough]]
* [[Fever]]
* [[Shortness of breath]]
* Nausea
===Complications===
Among the possible complications of Carbapenem-resistant ''enterobacteriaceae'' are the following:{{copy edit inline}}
* Kidney infection
* [[Lung abscess]]
* [[Sepsis]]

==Cause==
Three major classes of enzymes are involved in carbapenem resistance:<ref name=ref/>
* Class A carbapenemases, class B metallo-β-lactamases (MBL), and class D β-lactamases (OXA). The four known groups of class A carbapenemases are: SME , IMI , GES , and KPC .<ref name=PMID20537585/> At the UVA Medical Center, a transfer mechanism of KPC-dependent carbapenem resistance was discovered in the transmission of a plasmid carrying the transposon (Tn4401), which contains the KPC gene, to several bacteria including ''Enterobacter cloacae'', ''Klebsiella oxytoca'', ''E. coli'', and ''Citrobacter freundii''.<ref name="PMC3202755">{{Cite journal |last=Mathers |first=AJ |last2=Cox |first2=HL |last3=Kitchel |first3=B |last4=Bonatti |first4=H |last5=Brassinga |first5=AK |last6=Carroll |first6=J |last7=Scheld |first7=WM |last8=Hazen |first8=KC |last9=Sifri |first9=CD |year=2011 |title=Molecular Dissection of an Outbreak of Carbapenem-Resistant Enterobacteriaceae Reveals Intergenus KPC Carbapenemase Transmission through a Promiscuous Plasmid |journal=mBio |volume=2 |issue=6 |pages=e00204–11 |doi=10.1128/mBio.00204-11 |pmc=3202755 |pmid=22045989}}</ref>
* Class B metallo-β-lactamases (MBLs) are found largely in Gram-negative bacteria and environmental bacteria. The subclasses of MBL enzymes are B1, B2, and B3. MBLs have diverse enzymatic functions and have the ability to hydrolyze β-lactam antibiotics.
* Class D β-lactamases (OXA), which hydrolyze oxacillin, provide a good example of the variety of mechanisms that can be used to transfer resistance. The ''bla''<sub>OXA</sub> genes which encode OXA β-lactamases are found on both chromosomes and plasmids, and they have their natural reservoir in environmental bacteria and deep-sea microflora. Insertions in the vicinity of these genes have been shown to increase the strength of their promoters and increase resistance. Because of these characteristics, a wide geographic dissemination of OXA carbapenemase resistance in particular has occurred.<ref name=PMID20537585/>

==Risk factors==
[[File:Contaminated surfaces increase cross-transmission.jpg|thumb|right|450px| Contaminated surfaces increase cross-transmission]]
Hospitals are primary transmission sites for CRE-based infections. Up to 75% of hospital admissions attributed to CRE were from long-term care facilities or transferred from another hospital.<ref>{{Cite journal |last=Perez |first=F |last2=Van Duin |first2=D |year=2013 |title=Carbapenem-resistant Enterobacteriaceae: A menace to our most vulnerable patients |journal=Cleveland Clinic Journal of Medicine |volume=80 |issue=4 |pages=225–33 |doi=10.3949/ccjm.80a.12182 |pmc=3960994 |pmid=23547093}}</ref> Suboptimal maintenance practices are the largest cause of CRE transmission. This includes the failure to adequately clean and disinfect medication cabinets, other surfaces in patient rooms, and portable medical equipment, such as X-ray and ultrasound machines that are used for both CRE and non-CRE patients.<ref name="jstor10.1086/667738" />
Thus far, CRE have primarily been [[Hospital-acquired infection|nosocomial]] infectious agents. Almost all CRE infections occur in people receiving significant medical care in hospitals, long-term acute care facilities, or nursing homes.<ref name="CDC03513" /> Independent risk factors for CRE infection include use of [[beta-lactam antibiotics]] and the use of [[mechanical ventilation]]. Patients with [[diabetes]] have also been shown to be at an elevated risk for acquiring CRE infections.<ref name="jstor10.1086/667738">{{Cite journal |last=Chitnis |first=AS |last2=Caruthers |first2=PS |last3=Rao |first3=AK |last4=Lamb |first4=J |last5=Lurvey |first5=R |last6=Beau De Rochars |first6=V |last7=Kitchel |first7=B |last8=Cancio |first8=M |last9=Török |first9=TJ |last10=Guh |first10=Alice Y. |last11=Gould |first11=Carolyn V. |last12=Wise |first12=Matthew E. |display-authors=8 |year=2012 |title=Outbreak of carbapenem-resistant enterobacteriaceae at a long-term acute care hospital: Sustained reductions in transmission through active surveillance and targeted interventions |url=https://zenodo.org/record/1235704 |url-status=live |journal=Infection Control and Hospital Epidemiology |volume=33 |issue=10 |pages=984–92 |doi=10.1086/667738 |jstor=667738 |pmid=22961017 |s2cid=27480055 |archive-url=https://web.archive.org/web/20230312224016/https://zenodo.org/record/1235704 |archive-date=2023-03-12 |access-date=2023-03-12}}</ref>

When compared to other hospitalized patients, those admitted from long-term acute care facilities have significantly higher incidence of colonization and infection rates.<ref name="Choi">{{Cite journal |last=Choi |first=JP |last2=Cho, EH |last3=Lee, SJ |last4=Lee, ST |last5=Koo, MS |last6=Song, YG |year=2012 |title=Influx of multidrug resistant, Gram-negative bacteria in a public hospital among elderly patients from long-term care facilities: a single-center pilot study |journal=Archives of Gerontology and Geriatrics |volume=54 |issue=March–April |pages=19–22 |doi=10.1016/j.archger.2011.05.026 |pmid=21764147}}</ref> Another 2012 multicenter study found that over 30% of patients with recent exposure to LTAC were colonized or infected with CRE.<ref name="Call for Action">{{Cite journal |last=Savard |first=P |last2=Perl, TM |year=2012 |title=A call for action: managing the emergence of multidrug-resistant Enterobacteriaceae in the acute care settings |journal=Current Opinion in Infectious Diseases |volume=25 |issue=4 |pages=371–7 |doi=10.1097/QCO.0b013e3283558c17 |pmid=22766646 |s2cid=23670404}}</ref> A person susceptible to CRE transmission is more likely to be female, have a greater number of [[parenteral nutrition]]-days , and to have had a significant number of days breathing through a ventilator.<ref name="jstor10.1086/667738" />
Infections with carbapenem-resistant ''Klebsiella pneumoniae'' were associated with organ/stem cell transplantation, mechanical ventilation, exposure to antimicrobials, and overall longer length of stay in hospitals.<ref name="oxford" />
People most likely to acquire carbapenem-resistant bacteria are those already receiving medical attention.<ref name="oxford">{{Cite journal |last=Gupta |first=N. |last2=Limbago |first2=B. M. |last3=Patel |first3=J. B. |last4=Kallen |first4=A. J. |year=2011 |title=Carbapenem-Resistant Enterobacteriaceae: Epidemiology and Prevention |journal=Clinical Infectious Diseases |volume=53 |issue=1 |pages=60–7 |doi=10.1093/cid/cir202 |pmid=21653305 |doi-access=free}}</ref> In a study carried out at Sheba medical center, there was a trend toward worse [[Comorbidity#Charlson index|Charleson Comorbidity]] scores in patients who acquired CRKP during ICU stay.<ref>{{Cite journal |last=Debby |first=B.D. |last2=Ganor |first2=O. |last3=Yasmin |first3=M. |last4=David |first4=L. |last5=Nathan |first5=K. |last6=Ilana |first6=T. |last7=Dalit |first7=S. |last8=Smollan |first8=G. |last9=Galia |first9=R. |date=August 2012 |title=Epidemiology of carbapenem resistant Klebsiella pneumoniae colonization in an intensive care unit |journal=European Journal of Clinical Microbiology & Infectious Diseases |volume=31 |issue=8 |pages=1811–7 |doi=10.1007/s10096-011-1506-5 |pmid=22246509 |s2cid=18052294 |doi-access=free}}</ref> Those at highest risk are patients receiving an organ or stem cell implantation, use of mechanical ventilation, or have to have an extended stay in the hospital along with exposure to antimicrobials. A study performed in Singapore, on the acquisition of ertapenem-resistant Enterobacteriaceae to the acquisition of CRE.<ref>{{Cite journal |last=Teo |first=J |last2=Cai |first2=Y |last3=Tang |first3=S |last4=Lee |first4=W |last5=Tan |first5=TY |last6=Tan |first6=TT |last7=Kwa |first7=AL |year=2012 |editor-last=Spellberg |editor-first=Brad |title=Risk Factors, Molecular Epidemiology and Outcomes of Ertapenem-Resistant, Carbapenem-Susceptible Enterobacteriaceae: A Case-Case-Control Study |journal=PLOS ONE |volume=7 |issue=3 |pages=e34254 |bibcode=2012PLoSO...734254T |doi=10.1371/journal.pone.0034254 |pmc=3312905 |pmid=22461908 |doi-access=free}}</ref> revealed that exposure to antibiotics, especially fluoroquinolones and previous hospitalization dramatically increased the risk of acquisition carbapenem-resistant bacteria. This study found that carbapenem-resistant acquisition has a significantly higher mortality rate and poorer clinical response compared to that of the ertapenem-resistance acquisition.{{copy edit inline}}

Bacteruria caused by CRKp and CSKp have similar risk factors. These include prior antibiotic use, admittance to an ICU, use of a permanent urinary catheter, and previous invasive procedures or operations. A retrospective study of patients with CRKp and CSKp infection asserted that the use of [[cephalosporin]]s used before invasive procedures was higher in patients with CRKp infection, suggesting that it is a risk factor.<ref name="Shilo et al., 2013" />

In February 2015, the [[FDA]] reported about a transmission risk when people undergo a gastroenterology procedure called [[endoscopic retrograde cholangiopancreatography]], where an [[Upper endoscopy|endoscope]] enters the mouth, passes the stomach, and ends in the [[duodenum]]; if incompletely disinfected, the device can transmit CRE from one patient to another.<ref>{{Cite web |date=20 February 2015 |title=Design of Endoscopic Retrograde Cholangiopancreatography Duodenoscopes May Impede Effective Cleaning: FDA Safety Communication |url=http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm434871.htm |url-status=dead |archive-url=https://web.archive.org/web/20150220024405/http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm434871.htm |archive-date=20 February 2015 |access-date=13 April 2022 |website=fda.gov}}</ref> The FDA's safety communication came a day after the [[UCLA Health System]], Los Angeles, notified more than 100 patients that they may have been infected with CRE during endoscopies between October 2014 and January 2015.<ref>{{Cite news |last=Steve Gorman |date=20 February 2015 |title=L.A. hospital warns 179 patients possibly exposed to 'superbug' |url=https://www.reuters.com/article/us-usa-ucla-bacteria-idUSKBN0LN0ZS20150219 |url-status=live |archive-url=https://web.archive.org/web/20150220011923/http://www.reuters.com/article/2015/02/19/us-usa-ucla-bacteria-idUSKBN0LN0ZS20150219 |archive-date=20 February 2015 |access-date=20 February 2015 |work=Reuters}}</ref> The FDA had issued its first notice about the devices in 2009.<ref>{{Cite news |last=Sharon Begley, Toni Clarke |date=20 February 2015 |title=FDA knew devices spread fatal 'superbug' but does not order fix |url=https://www.reuters.com/article/us-usa-ucla-devices-idUSKBN0LO02Q20150220 |url-status=live |archive-url=https://web.archive.org/web/20150220020020/http://www.reuters.com/article/2015/02/20/us-usa-ucla-devices-idUSKBN0LO02Q20150220 |archive-date=20 February 2015 |access-date=20 February 2015 |work=Reuters}}</ref>

==Mechanism==
[[File:Penicillin inhibition.svg|thumb|305px|upright|right|Penicillin and most other β-lactam antibiotics act by inhibiting penicillin-binding proteins, which normally catalyze cross-linking of bacterial cell walls.<ref name=":31939154">{{Cite book |last=Miyachiro |first=Mayara M. |url=https://link.springer.com/chapter/10.1007/978-3-030-28151-9_8 |title=Macromolecular Protein Complexes II: Structure and Function |last2=Contreras-Martel |first2=Carlos |last3=Dessen |first3=Andréa |date=2019 |publisher=Springer International Publishing |isbn=978-3-030-28151-9 |pages=273–289 |language=en |chapter=Penicillin-Binding Proteins (PBPs) and Bacterial Cell Wall Elongation Complexes |access-date=2024-09-15 |archive-date=2023-02-12 |archive-url=https://web.archive.org/web/20230212035746/https://link.springer.com/chapter/10.1007/978-3-030-28151-9_8 |url-status=live }}</ref>]]
===Antibiotic function===
The [[β-lactam]] family of antibiotic molecules consists of four groups: penicillins, cephalosporins, carbapenems and monobactams.<ref name="liamandtyler">{{Cite journal |last=Nordman |first=P |last2=Dortet L |last3=Poirel L |date=May 2012 |title=Carbapenem resistance in Enterobacteriaceae: here is the storm! |journal=Trends in Molecular Medicine |volume=18 |issue=5doi=10.1016/j.molmed.2012.03.003 |pages=263–72 |doi=10.1016/j.molmed.2012.03.003 |pmid=22480775}}</ref>

These antibiotics share common structure and mechanism of action. They enter the [[periplasmic space]] through [[porins]], where they then inhibit [[DD-transpeptidase|transpeptidases]] , enzymes that facilitate peptide cross-links during cell wall synthesis. Their binding to the PBP active site is facilitated in part by their common structure, which is similar to that of D-alanyl-D-alanine. D-alanyl-D-alanine is a residue on the NAM peptide subunit involved in building [[peptidoglycan]].<ref name="liamandtyler" />

Carbapenem covalently binds to PBPs, which causes transpeptidases to irreversibly lose their catalytic activity.<ref name="liamandtyler" />

Inhibition of transpeptidases prevents the formation of cross-links between peptidoglycan polymers and causes a build-up of peptidoglycan precursors. Newly formed peptidoglycan is weakened from the absence of cross-linkages.
The continued activity of [[autolysins]], that function like lysozymes and cleave glycosidic and peptide bonds of peptidoglycan in periplasm, weakens the cell wall and leads to osmotic bursting of the bacterial cell.{{copy edit inline}}

A unique quality of carbapenems is their resistance to hydrolysis by bacterial plasmid and chromosomally mediated extended-spectrum β-lactamases (ESBL).<ref>{{Cite journal |last=Martin |first=SI |last2=Kaye |first2=KM |year=2004 |title=Beta-lactam antibiotics: newer formulations and newer agents |journal=Infectious Disease Clinics of North America |volume=18 |issue=3 |pages=603–619 |doi=10.1016/j.idc.2004.04.006 |pmid=15308278}}</ref>

===Carbapenem resistance===
[[File:Carbapenem-resistant enterobacteriaceae.webp|thumb|left|550px|Mechanism of drug resistance(Carbapenem-resistant ''Enterobacteriaceae'')
<ref>{{Cite journal |last=Bologna |first=Eugenio |last2=Licari |first2=Leslie Claire |last3=Manfredi |first3=Celeste |last4=Ditonno |first4=Francesco |last5=Cirillo |first5=Luigi |last6=Fusco |first6=Giovanni Maria |last7=Abate |first7=Marco |last8=Passaro |first8=Francesco |last9=Di Mauro |first9=Ernesto |last10=Crocetto |first10=Felice |last11=Pandolfo |first11=Savio Domenico |last12=Aveta |first12=Achille |last13=Cilio |first13=Simone |last14=Di Filippo |first14=Isabella |last15=Barone |first15=Biagio |date=26 January 2024 |title=Carbapenem-Resistant Enterobacteriaceae in Urinary Tract Infections: From Biological Insights to Emerging Therapeutic Alternatives |url=https://pubmed.ncbi.nlm.nih.gov/38399502/ |journal=Medicina (Kaunas, Lithuania) |volume=60 |issue=2 |pages=214 |doi=10.3390/medicina60020214 |issn=1648-9144 |last16=Franco |first16=Antonio |last17=Arcaniolo |first17=Davide |last18=La Rocca |first18=Roberto |last19=Pinchera |first19=Biagio |last20=Napolitano |first20=Luigi |access-date=15 September 2024 |archive-date=6 June 2024 |archive-url=https://web.archive.org/web/20240606201727/https://pubmed.ncbi.nlm.nih.gov/38399502/ |url-status=live }}</ref>]]

In general, carbapenem, a [[β-lactam antibiotic]], targets cells by inhibiting [[DD-transpeptidase|transpeptidases]] . This prevents synthesis of [[peptidoglycan]], a necessary structural component, leading to cell lysis. Resistance to carbapenem among [[Gram-negative bacteria]] in general can be acquired through several mechanisms.<ref name="su">{{Cite journal |last=Suay-García |first=Beatriz |last2=Pérez-Gracia |first2=María Teresa |date=19 August 2019 |title=Present and Future of Carbapenem-resistant Enterobacteriaceae (CRE) Infections |url=https://pubmed.ncbi.nlm.nih.gov/31430964/ |journal=Antibiotics (Basel, Switzerland) |volume=8 |issue=3 |pages=122 |doi=10.3390/antibiotics8030122 |issn=2079-6382 |accessdate=15 September 2024 |archive-date=26 August 2024 |archive-url=https://web.archive.org/web/20240826214356/https://pubmed.ncbi.nlm.nih.gov/31430964/ |url-status=live }}</ref>{{clarification needed}}
* Active transport of carbapenem drugs out of the cell, augmented drug [[Efflux (microbiology)|efflux]], has been observed in some resistant species.<ref name=su/>{{clarification needed}}
* One mechanism of resistance is mutation in or loss of outer membrane [[Porin (protein)|porins]], preventing antibiotics from entering the cells.<ref name="Little">{{Cite journal |last=Little |first=ML |last2=Qin |first2=X |last3=Zerr |first3=DM |last4=Weissman |first4=SJ |year=2012 |title=Molecular diversity in mechanisms of carbapenem resistance in paediatric Enterobacteriaceae |journal=International Journal of Antimicrobial Agents |volume=39 |issue=1 |pages=52–57 |doi=10.1016/j.ijantimicag.2011.09.014 |pmc=3237943 |pmid=22055532}}</ref> Changes within the porin protein gene cause a [[frameshift mutation|frameshift]], altering the porin structure and function.<ref name=Little/> Changes in the porin protein hinder the diffusion of carbapenem and other antibiotics into the periplasm.<ref name="Logan">{{Cite journal |last=Logan |first=LK |year=2012 |title=Carbapenem-resistant enterobacteriaceae: an emerging problem in children |journal=Clinical Infectious Diseases |volume=55 |issue=6 |pages=852–859 |doi=10.1093/cid/cis543 |pmid=22700827 |doi-access=free}}</ref> Bacteria that express plasmid-borne [[β-lactamase|extended-spectrum β-lactamases (ESBL)]] can become carbapenem-resistant if an [[insertion sequence]] or four-nucleotide duplication is present within chromosomal genes for outer membrane porin proteins.<ref name=Little/> ''Klebsiella pneumoniae'' has been associated with the lack of outer membrane porin proteins, OmpK35 and OmpK36. The loss of OmpK36 porins can be attributed to point mutations that result in premature termination of translation, resulting in a truncated and consequently nonfunctional protein.<ref name="Magical Pink Fluffy Microbes">{{Cite journal |last=Shin |first=So Youn |last2=Bae |first2=IK |last3=Kim |first3=J |last4=Jeong |first4=SH |last5=Yong |first5=D |last6=Kim |first6=JM |last7=Lee |first7=K |year=2012 |title=Resistance to carbapenems in sequence type 11 ''Klebsiella pneumoniae'' is related to DHA-1 and loss of OmpK35 and/or OmpK36 |journal=Journal of Medical Microbiology |volume=61 |issue=Pt 2 |pages=239–245 |doi=10.1099/jmm.0.037036-0 |pmid=21940650}}</ref> These outer membrane proteins are involved in the transfer of the antimicrobial genetic material in the cell. Loss of either OmpK35 and OmpK36 or only OmpK36<ref name="Magical Pink Fluffy Microbes" /> leads to carbapenem resistance. In ''Klebsiella pneumoniae'', the lack of either OmpK35 or OmpK36 leads to carbapenem resistance, but with the lack of both proteins, a high level of resistance is present.<ref name="Sho">{{Cite journal |last=Sho |first=Takehiko |last2=Tetsuro Muratani |last3=Ryoichi Hamasuna |last4=Hiroko Yakushiji |last5=Naohiro Fujimoto |last6=Tetsuro Matsumoto |year=2013 |title=The Mechanism of High-Level Carbapenem Resistance in ''Klebsiella pneumoniae'': Underlying Ompk36-Deficient Strains Represent a Threat of Emerging High-Level Carbapenem-Resistant K. pneumoniae with IMP-1 β-Lactamase Production in Japan |journal=Microbial Drug Resistance |volume=19 |issue=4 |pages=274–81 |doi=10.1089/mdr.2012.0248 |pmid=23514607}}</ref> An observed 32- to 64-fold increase in [[minimum inhibitory concentration]]s occurs for the carbapenems when both proteins are not expressed.<ref name=Sho/>
* CRE produce carbapenemases, a form of β-lactamase.<ref name="Magical Pink Fluffy Microbes" /> These enzymes cleave the β-lactam ring, an essential component of β-lactam antibiotics that are recognized by and bound to PBPs. Carbapenemases are divided into different classes, depending on the structure of the enzyme and the mechanism by which they hydrolyze the β-lactam ring. The two broad categories of carbapenemases are serine-carbopenemases, which contain serine at the active site, and metallocarbapenemases, which contain zinc at the active site. Class A carbapenemases are serine carbapenemases and are encoded on either the chromosome of the bacteria or a plasmid. A serine at position 70 at the active site of this class of enzymes is required for hydrolysis of β-lactams to occur. Class D carbapenemases, also referred to as the OXA β-lactamases, are serine β-lactamases. They are encoded on plasmids and contain a large variability in amino acid sequence. The resistance mechanism for class D carbapenemases is caused by the formation of an acyl intermediate when breaking the β-lactam ring. Class B carbapenemases are metallolactamases and require a zinc at the active site for hydrolysis.<ref name="Here is the Storm!">{{Cite journal |last=Nordmann |first=Patrice |display-authors=etal |date=May 2012 |title=Carbapenem resistance in Enterobacteriaceae: here is the storm! |journal=Trends in Molecular Medicine |volume=18 |issue=5 |pages=263–272 |doi=10.1016/j.molmed.2012.03.003 |pmid=22480775}}</ref><ref name="Carbapenemases">{{Cite journal |last=Queenan |first=Anne Marie |last2=Karen Bush |date=July 2007 |title=Carbapenemases: the Versatile β-Lactamases |journal=Clinical Microbiology Reviews |volume=20 |issue=3 |pages=440–458 |doi=10.1128/CMR.00001-07 |pmc=1932750 |pmid=17630334}}</ref><ref>{{Cite journal |last=Patel |first=Gopi |last2=Bonomo |date=March 2013 |title="Stormy waters ahead": global emergence of carbapenemases |journal=Frontiers in Microbiology |volume=4 |pages=48 |doi=10.3389/fmicb.2013.00048 |pmc=3596785 |pmid=23504089 |doi-access=free}}</ref>

CR ''Pseudomonas aeruginosa'' is commonly present in intensive-care units, and can lead to dangerous infections.<ref name="ncbi" /> In Thai hospitals, of 261 multidrug-resistant samples collected of ''P. aeruginosa'' , 71.65% were carbapenem-resistant.<ref name="ncbi">{{Cite journal |last=Khuntayaporn |first=P |last2=Montakantikul |first2=P |last3=Mootsikapun |first3=P |last4=Thamlikitkul |first4=V |last5=Chomnawang |first5=MT |year=2012 |title=Prevalence and genotypic relatedness of carbapenem resistance among multidrug-resistant P. aeruginosa in tertiary hospitals across Thailand |journal=Annals of Clinical Microbiology and Antimicrobials |volume=11 |pages=25 |doi=10.1186/1476-0711-11-25 |pmc=3475077 |pmid=22970983}}</ref>

===Transfer between bacteria===
[[File:Horizontal transfer.webp|thumb|right|450px|Horizontal gene transfer by extended-spectrum β-lactamase producing ''Enterobacteriaceae''<ref>{{Cite journal |last=Husna |first=Asmaul |last2=Rahman |first2=Md Masudur |last3=Badruzzaman |first3=A. T. M. |last4=Sikder |first4=Mahmudul Hasan |last5=Islam |first5=Mohammad Rafiqul |last6=Rahman |first6=Md Tanvir |last7=Alam |first7=Jahangir |last8=Ashour |first8=Hossam M. |date=30 October 2023 |title=Extended-Spectrum β-Lactamases (ESBL): Challenges and Opportunities |url=https://pubmed.ncbi.nlm.nih.gov/38001938/ |journal=Biomedicines |volume=11 |issue=11 |pages=2937 |doi=10.3390/biomedicines11112937 |issn=2227-9059 |access-date=15 September 2024 |archive-date=3 June 2024 |archive-url=https://web.archive.org/web/20240603162342/https://pubmed.ncbi.nlm.nih.gov/38001938/ |url-status=live }}</ref>]]
Gram-negative bacteria can develop and transfer β-lactam resistance in many ways. They can generate new extended-spectrum β-lactamases (ESBL) from the existing spectrum of plasmid-mediated β-lactamases through amino acid substitution. They can acquire genes encoding ESBL from environmental bacteria. They can increase the expression of chromosome-encoded β-lactamase genes (''bla'' genes) due to regulatory gene and promoter sequence modifications. They can mobilize ''bla'' genes through integrons or horizontal transfer of genomic islands into other Gram-negative species and strains.<ref>{{Cite journal |last=Hudson |first=Corey |last2=Bent |first2=Zachary |last3=Meagher |first3=Robert |last4=Williams |first4=Kelly |date=June 6, 2014 |title=Resistance Determinants and Mobile Genetic Elements of an NDM-1-Encoding ''Klebsiella pneumoniae'' Strain |journal=PLOS ONE |volume=9 |issue=6 |pages=e99209 |bibcode=2014PLoSO...999209H |doi=10.1371/journal.pone.0099209 |pmc=4048246 |pmid=24905728 |doi-access=free}}</ref><ref>{{Cite journal |last=Pulcrano |first=G |last2=Pignanelli |first2=S |last3=Vollaro |first3=A |last4=Esposito |first4=M |last5=Iula |first5=VD |last6=Roscetto |first6=E |last7=Soriano |first7=AA |last8=Catania |first8=MR |date=Jun 2016 |title=Isolation of Enterobacter aerogenes carrying blaTEM-1 and blaKPC-3 genes recovered from a hospital Intensive Care Unit |journal=APMIS |volume=124 |issue=6 |pages=516–21 |doi=10.1111/apm.12528 |pmid=27004836 |s2cid=33234690}}</ref> They can disseminate plasmid-mediated carbapenemases. Finally, they can lower or even inhibit the expression of porin genes.<ref name="PMID20537585">{{Cite journal |last=Pfeifer |first=Yvonne |last2=Cullik |first2=Angela |last3=Witte |first3=Wolfgang |date=Aug 2010 |title=Resistance to cephalosporins and carbapenems in Gram-negative bacterial pathogens |journal=Int J Med Microbiol |volume=300 |issue=6 |pages=371–9 |doi=10.1016/j.ijmm.2010.04.005 |pmid=20537585}}</ref>

The facilitated spread of carbapenem resistance appears to have multiple origins and repeated introduction into the UK of bacteria with the ''bla''<sub>OXA-48</sub> gene via horizontal transfer of similar plasmids to pOXA-48a. A recent study in the UK examined 26 isolates of Enterobacteriaceae consisting of a diverse set of sequence types (ST) of ''K. pneumoniae'', ''E. coli'', and ''Enterobacter cloacae'' producing OXA-48-like carbapenemases.{{copy edit inline}} Their findings included:
* 25 of the 26 strains had the ''bla''<sub>OXA-48</sub> gene.
** 21 of these isolates had resistance plasmids that could be transferred by conjugation; 20 of these transformants had the three functional genes, ''repA'', ''traU'', and ''parA'' found in pOXA-48a.{{copy edit inline}}
** In ST38 ''E. coli'', no OXA-48 transconjugants were found and it only had the ''parA'' gene.{{copy edit inline}}
* The Indian strain of ''K. pneumonia'' had an OXA-181-encoding plasmid and also could not be transferred by conjugation and had none of the three functional genes found in pOXA-48a.<ref name="PMID22532467">{{Cite journal |last=Dimou |first=V |last2=Dhanji |first2=H |last3=Pike |first3=R |last4=Livermore |first4=DM |last5=Woodford |first5=N |year=2012 |title=Characterization of Enterobacteriaceae producing OXA-48-like carbapenemases in the UK |journal=The Journal of Antimicrobial Chemotherapy |volume=67 |issue=7 |pages=1660–5 |doi=10.1093/jac/dks124 |pmid=22532467 |doi-access=free}},</ref>

====Gram-negative bacteria====
Outer membrane vesicles (OMVs), that can transfer DNA between bacterial cells, are produced by metabolically active bacterial cells, and the OMVs are not the result of cell lysis or cell death. Pathogenic strains can produce about 10-25 times more vesicles than a nonpathogenic strain making this highly relevant to carbapenem resistance transfer.<ref name="yo">{{Cite journal |last=Rumbo |first=Carlos |last2=Fernández-Moreira |first2=E |last3=Merino |first3=M |last4=Poza |first4=M |last5=Mendez |first5=JA |last6=Soares |first6=NC |last7=Mosquera |first7=A |last8=Chaves |first8=F |last9=Bou |first9=G |date=July 2011 |title=Horizontal transfer of the OXA-24 carbapenemase gene via outer membrane vesicles: a new mechanism of dissemination of carbapenem resistance genes in Acinetobacter baumanni |journal=Antimicrobial Agents and Chemotherapy |series=7 |volume=55 |issue=7 |pages=3084–3090 |doi=10.1128/AAC.00929-10 |pmc=3122458 |pmid=21518847}}</ref> OMVs protect plasmids from being digested extracellularly by nucleases that may be found in the environment, thus favoring [[horizontal gene transfer]].<ref name="yo" />

==Diagnosis==
Carbapenem-resistant Enterobacteriaceae (CRE) have been defined as carbapenem-nonsusceptible and extended-spectrum cephalosporin-resistant ''[[Escherichia coli]], [[Enterobacter aerogenes]], [[Enterobacter cloacae]]'' complex, ''[[Klebsiella pneumoniae]]'', or ''[[Klebsiella oxytoca]]''. Some exclude ertapenem resistance from the definition.<ref name="jama">{{Cite journal |last=Guh Alice Y. |last2=Bulens Sandra N. |last3=Mu Yi |last4=Jacob Jesse T. |last5=Reno Jessica |display-authors=etal |year=2015 |title=Epidemiology of Carbapenem-Resistant Enterobacteriaceae in 7 US Communities, 2012-2013 |journal=JAMA |volume=314 |issue=14 |pages=1479–87 |doi=10.1001/jama.2015.12480 |pmc=6492240 |pmid=26436831}}</ref>
===Agar plate method===

Variations are seen in the media used for inoculation. Many studies use media with 1 to 2&nbsp;mg/L of imipenem. However, bacteria that produce OXA-48 or OXA-181 result in low-level resistance, which cannot be detected efficiently due to the high concentration.<ref name="Salvani">{{Cite journal |last=Landman |first=D |last2=Salvani, JK |last3=Bratu, S |last4=Quale, J |date=November 2005 |title=Evaluation of techniques for detection of carbapenem-resistant ''Klebsiella pneumoniae'' in stool surveillance cultures |journal=Journal of Clinical Microbiology |volume=43 |issue=11 |pages=5639–41 |doi=10.1128/JCM.43.11.5639-5641.2005 |pmc=1287836 |pmid=16272497}}</ref>
Therefore, more recent screening media use broth containing 0.5–1&nbsp;mg/L [[imipenem]] or 0.5&nbsp;mg/L [[ertapenem]]. The downsides to this approach include the delay of results from the inoculation and the inability to identify the type of carbapenemase.{{copy edit inline}}

===Disc diffusion method===

The disc diffusion method can be used by hospital laboratories to screen for CRE. In this technique, antibiotic discs are placed onto plates of Mueller Hinton agar that have already been inoculated with the sample strain. The plates are then incubated overnight at 37&nbsp;°C. Following incubation, the zones of inhibition surrounding the various antibiotic discs are measured and compared with Clinical and Laboratory Standard Institute guidelines. Identification of KPCs, MBLs and OXAs can be achieved by demonstrating synergistic inhibition with phenyl boronic acid, EDTA or neither, respectively.<ref>{{Cite journal |last=Pournaras S |display-authors=et al |year=2013 |title=A Combined Disk Test for Direct Differentiation of Carbapenemase-Producing Enterobacteriaceae in Surveillance Rectal Swabs |journal=J Clin Microbiol |volume=51 |issue=9 |pages=2986–90 |doi=10.1128/JCM.00901-13 |pmc=3754636 |pmid=23843486}}</ref>

===PCR method===
[[File:PCR masina kasutamine.jpg|thumb|right|450px|PCR]]
PCR-based screening methodologies are in the process of development for a number of genes responsible for resistance. They speed up detection and can readily differentiate between carbapenamase genes-sometimes in a multiplex format. Costs of PCR testing are decreasing and reliability of molecular based tests relates more to gene presence and gene expression for production of the relevant carbapenamase. Nested arbitrary PCR (ARB-PCR) was used during a 2007 CRE outbreak at the University of Virginia Medical Center to identify the specific ''bla'' KPC plasmid involved in the transmission of the infection, and researchers suggest that ARB-PCR may also be used to identify other methods of CRE spread.<ref name="PMC3202755" />

===MALDI-TOF MS===
MALDI-TOF MS can detect changes in mass to charge ratios. Cabapenem-resistant bacteria often employ β-lactamases, which physically disrupt the structure of β-lactam antibiotics. Since this causes a change in the mass of the antibiotic, resistant bacteria are detectable by MALDI-TOF MS. Accepted clinical tests often require an overnight incubation before reading the result, but MALDI-TOF MS can return results in just 4–5 hours.{{copy edit inline}}

MALDI-TOF cannot detect resistant bacteria, which do not physically disrupt the β-lactam antibiotic, i.e. where no mass change occurs. Therefore, the method serves best as a first screen for patients admitted to the hospital, but should be followed with secondary testing.<ref name="Sparbier">{{Cite journal |last=Sparbier |first=Katrin |last2=Schubert |first2=S |last3=Weller |first3=U |last4=Boogen |first4=C |last5=Kostrzewa |first5=M |date=May 2012 |title=Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry-Based FUnctional Assay for Rapid Detection of Resistance against B-Lactam Antibiotics |journal=Journal of Clinical Microbiology |volume=50 |issue=3 |pages=927–937 |doi=10.1128/JCM.05737-11 |pmc=3295133 |pmid=22205812}}</ref>

===Differential diagnosis===
In terms of the DDx for Carbapenem-resistant ''enterobacteriaceae'' we find the following:{{copy edit inline}}
* [[Methicillin-resistant Staphylococcus aureus|Methicillin-resistant ''Staphylococcus aureus'']]
* Vancomycin-resistant ''Enterococci''
* several other Gram-negative bacteria

==Prevention==
[[File:Hand washing man.jpg|thumb|right|450px|Hand hygiene is very important to avert CRE<ref name=jama/>]]
Researchers found environmental reservoirs of CRE bacteria in ICU sinks and drains. Despite multiple attempts to sterilize these sinks and drains, using detergents and steam, the hospital staff was unsuccessful in getting rid of the CRE. Due to the bacterial resistance to cleaning measures, staff should take extreme precaution in maintaining sterile environments in hospitals not yet infected with the CRE-resistant bacteria.<ref name="Down the drain" />

A major means of transmission is through sinks, so staff should take extra precaution in maintaining sterile conditions. Hospitals could reduce transmission by creating sinks with designs that could reduce backsplash. Another method to reduce transmission from sink to sink is to have sink brushes in each room that would be for cleaning that individual sink alone. Hospital staff should be trained to never dispose of clinical waste down the sinks in patient rooms. A hospital in Melbourne, Australia, implemented similar strategies as these to reduce transmission and prevent further infection of more ICU patients.
Armed with the knowledge of their status as CRE transmission sites, hospitals must take special care to monitor CRE outbreaks within their wards. Efficient and accurate detection of CRE is the first step.
Enterobacteriaceae are most commonly found in the intestinal flora. Using stool and rectal swabs are, thus, the most reliable methods for testing resistance.<ref name="Down the drain" />

One method found effective is to screen and isolate incoming patients from other facilities, and renew focus on [[hand washing]]. No new drugs for the bacteria are in development and the bacteria's rapid adaptation to new drugs makes investment in their development unprofitable, as the new drug would quickly become useless.<ref name=USAtoday/> Studies have found that CRE incidence and prevalence can be reduced by applying targeted interventions including increased hygiene measures and equipment sterilization, even in populations where the prevalence of infection exceeds 50% of patients.<ref name="jstor10.1086/667738" /> However, additional environmental cleaning to control transmission has not been verified by controlled trials.<ref name="cre91">{{Cite journal |last=Kahn |first=A. S. |last2=Dancer, Humphreys |date=October 2012 |title=Priorities in the prevention and control of multidrug-resistant Enterobacteriaceae in hospitals |journal=Journal of Hospital Infection |volume=82 |issue=2 |pages=85–93 |doi=10.1016/j.jhin.2012.06.013 |pmid=22863084}}</ref>

Prevention is a top priority for reducing person-to-person transmission of CRE. This is especially true because limited treatment options are available to use after carbapenem resistance develops. Most current research calls for a coordinated, multifaceted approach to infection prevention and containment, and the Centers for Disease Control and Prevention have issued preliminary guidelines for the control of CRE transmission.<ref name="CDC ICG">{{Cite web |date=2019-11-04 |title=CDC Infection Control Guidelines |url=https://www.cdc.gov/hai/organisms/cre/cre-toolkit/ |url-status=live |archive-url=https://web.archive.org/web/20220119103745/https://www.cdc.gov/hai/organisms/cre/cre-toolkit/ |archive-date=2022-01-19 |access-date=2023-03-12}}</ref> Experts advocate for a proactive approach, based on the belief that it will be most cost-effective to combat the problem before it is established. However, when immediate financial and personnel resources are limited, healthcare administrators may be forced to respond reactively, aiming to reduce any further transmission.<ref>{{Cite journal |last=Bilavsky |first=E |last2=Schwaber |first2=MJ |last3=Carmeli |first3=Y |year=2010 |title=How to stem the tide of carbapenemase-producing enterobacteriaceae?: Proactive versus reactive strategies |journal=Current Opinion in Infectious Diseases |volume=23 |issue=4 |pages=327–31 |doi=10.1097/QCO.0b013e32833b3571 |pmid=20581673 |s2cid=20036704}}</ref>

Although a consensus exists for the need of prevention protocols, infection control practices often vary among hospitals, even within close geographic area. In a survey of 15 hospitals within the Toronto area, many hospitals employed varying combinations of basic infection control practices. Eight different practices were observed among the 15 hospitals, some of which included in the most recent publication of guidelines from the [[Public Health Agency of Canada]].<ref name="Canada PHAC">{{Cite web |date=2010-11-12 |title=Canadian Public Health Infection Prevention Guidelines |url=http://www.phac-aspc.gc.ca/nois-sinp/guide/ipcm-mpci/ipcm-mpci-eng.php |url-status=live |archive-url=https://web.archive.org/web/20170620053404/http://www.phac-aspc.gc.ca/nois-sinp/guide/ipcm-mpci/ipcm-mpci-eng.php |archive-date=2017-06-20 |access-date=2023-03-12}}</ref> Some of these recommendations include laboratory testing, active surveillance, screening, hand hygiene, [[personal protective equipment]], environmental cleaning, laundry waste management, and isolation with dedicated equipment and nursing staff. However, only five hospitals had written policies describing how to respond to an outbreak.<ref>{{Cite journal |last=Lowe |first=C |last2=Katz |first2=K |last3=McGeer |first3=A |last4=Muller |first4=MP |last5=Toronto Esbl Working |first5=Group |year=2012 |title=Disparity in infection control practices for multidrug-resistant Enterobacteriaceae |journal=American Journal of Infection Control |volume=40 |issue=9 |pages=836–9 |doi=10.1016/j.ajic.2011.11.008 |pmid=22361360}}</ref>

An infection control plan was implemented at the Kaplan Medical Center in Israel to control a hospital outbreak of carbapenem-resistant ''K. pneumoniae.'' The comprehensive plan included guidelines for cohorting patients in separate locations, cleaning with 1,000 ppm [[hypochlorite]], screening for isolates from rectal swabs, and distribution of educational instruction sheets, lectures for all medical staff, and training. The hospital also implemented an automated computer system that updated patient charts when new cases were reported, if patients were carriers, and what precautions to take when dealing with such patients. This plan was evaluated in a quasiexperimental study through the incidence of clinical cases, the rate of cross-infection, and the rate of screening for carriage in admitted patients with increased risk of carriage. The study had a 16-fold decrease in the incidence of resistant ''K. pneumoniae'', which was sustained for 30 months. The plan can provide a model for other hospitals to contain outbreaks of carbapenem-resistant bacteria.<ref>{{Cite journal |last=Ciobotaro |first=P |last2=Oved, M |last3=Nadir, E |last4=Bardenstein, R |last5=Zimhony, O |date=October 2011 |title=An effective intervention to limit the spread of an epidemic carbapenem-resistant ''Klebsiella pneumoniae'' strain in an acute care setting: from theory to practice |journal=American Journal of Infection Control |volume=39 |issue=8 |pages=671–7 |doi=10.1016/j.ajic.2011.05.004 |pmid=21864942}}</ref> A reduction in the use of unnecessary invasive devices, including urinary catheters, could help reduce CRE transmission.<ref name="jstor10.1086/667738" />

Several methods have been tested for their effectiveness at improving thorough intensive-care unit environmental hygiene. A study conducted in 2010 across 3532 high risk environmental surfaces in 260 intensive care unit rooms in 27 acute-care hospitals (ICUs) assessed the consistency at which these surfaces met base line cleaning standards. Only 49.5% of the high-risk object surfaces were found to meet this baseline criterion. The least-cleaned objects were bathroom light switches, room door knobs, and bed pan cleaners. Significant improvements in ICU room cleaning was achieved through a structured approach that incorporated a simple, highly objective surface targeting method and repeated performance feedback to environmental surface personnel. Specific methods included implementing an objective evaluation process, environmental surfaces staff education, programmatic feedback, and continuous training to minimize the spread of hospital-associated infections. The authors noted an improvement in the thoroughness of cleaning at 71% from baseline for the entire group of hospitals involved.<ref name="Carling">{{Cite journal |last=Carling |first=Philip C. |last2=Michael F. Parry |last3=Lou Ann Bruno-Murtha |last4=Brian Dick |year=2010 |title=Improving environmental hygiene in 27 intensive care units to decrease multidrug-resistant bacterial transmission |journal=Critical Care Medicine |volume=38 |issue=4 |pages=1054–1059 |doi=10.1097/CCM.0b013e3181cdf705 |pmid=20081531 |s2cid=16166524}}</ref>

==Treatments==
[[File:Fosfomycin 3D ball.png|thumb|right|350px|Fosfomycin ]]
Several antimicrobial drugs have been tested for the effective treatment of CRE. [[Fosfomycin]] is an antimicrobial agent that acts to inhibit [[UDP-N-acetylglucosamine enolpyruvyl transferase]] (MurA) which catalyzes one of the early steps of bacterial cell wall synthesis, and is effective against Gram-negative and -positive aerobic bacteria, such as CRE. A meta-analysis of 17 studies investigating the clinical effectiveness of fosfomycin in four multidrug-resistant strains of Enterobacteriaceae found 11 which reported that over 90% of bacterial isolates were susceptible to fosfomycin.<ref name=ref/><ref>{{Cite journal |last=Morrill |first=Haley J. |last2=Pogue |first2=Jason M. |last3=Kaye |first3=Keith S. |last4=LaPlante |first4=Kerry L. |date=5 May 2015 |title=Treatment Options for Carbapenem-Resistant Enterobacteriaceae Infections |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4462593/ |url-status=live |journal=Open Forum Infectious Diseases |volume=2 |issue=2 |pages=ofv050 |doi=10.1093/ofid/ofv050 |issn=2328-8957 |archive-url=https://web.archive.org/web/20240225132626/https://ncbi.nlm.nih.gov/pmc/articles/PMC4462593/ |archive-date=25 February 2024 |access-date=13 September 2024}}</ref>{{clarification needed}}

The elevated level of antimicrobial activity by fosfomycin can be attributed to the fact that resistance to this antibiotic in Enterobacteriaceae is chromosomally encoded and not plasmid-mediated. This causes a decreased capacity for survival in the bacteria. Bacteria that are naturally resistant to fosfomycin are less robust and less pathogenic.<ref name="Fosfomycin">{{Cite journal |last=Falagas |first=ME |last2=Kastoris |first2=AC |last3=Kapaskelis |first3=AM |last4=Karageorgopoulos |first4=DE |year=2010 |title=Fosfomycin for the treatment of multidrug-resistant, including extended-spectrum beta-lactamase producing, Enterobacteriaceae infections: A systematic review |journal=The Lancet Infectious Diseases |volume=10 |issue=1 |pages=43–50 |doi=10.1016/S1473-3099(09)70325-1 |pmid=20129148}}</ref>

[[Tigecycline]], a member of the glycylcyclines antibiotics, has proven to be an effective therapy against Enterobacteriaceae that typically display [[tetracycline]] resistance,<ref>{{Cite web |title=Tigecycline - Infectious Diseases |url=https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-drugs/tigecycline |url-status=live |archive-url=https://web.archive.org/web/20190808085134/https://www.merckmanuals.com/professional/infectious-diseases/bacteria-and-antibacterial-drugs/tigecycline |archive-date=2019-08-08 |access-date=2019-09-26 |website=Merck Manuals Professional Edition |language=en-US}}</ref> because tigecycline has a higher binding affinity with ribosomal sites than tetracycline has.Tigecycline is capable of killing almost all of the ESBLs and multidrug-resistant (MDR) ''E. coli'' isolates and the large majority of ESBL and MDR isolates of ''Klebsiella'' species.<ref name="kel">{{Cite journal |last=Kelesidis |first=Theodoros |last2=Karageorgopoulos |first2=Drosos E. |last3=Kelesidis |first3=Iosif |last4=Falagas |first4=Matthew E. |date=November 2008 |title=Tigecycline for the treatment of multidrug-resistant Enterobacteriaceae: a systematic review of the evidence from microbiological and clinical studies |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8445635/#:~:text=Tigecycline%20is%20microbiologically%20active%20against%20almost%20all%20of,majority%20of%20ESBL%20or%20MDR%20Klebsiella%20spp.%20isolates. |url-status=live |journal=Journal of Antimicrobial Chemotherapy |volume=62 |issue=5 |pages=895–904 |doi=10.1093/jac/dkn311 |issn=0305-7453 |archive-url=https://web.archive.org/web/20220811095026/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8445635/#:~:text=Tigecycline%20is%20microbiologically%20active%20against%20almost%20all%20of,majority%20of%20ESBL%20or%20MDR%20Klebsiella%20spp.%20isolates. |archive-date=2022-08-11 |access-date=2024-09-13}}</ref>{{clarification needed|date=February 2015}}

A 2008 review of 42 studies of ''in vitro'' susceptibility of bacteria to tigecycline showed that MDR ''K. pneumoniae'' and ''E. coli'', including those that were carbapenem resistant, were susceptible more than 90% of the time. A limited number of patients have been treated with tigecycline, but the FDA has approved it in certain cases with synergies of other drugs. The limited number of patients indicates that more trials are needed to determine the overall clinical effectiveness.<ref name=kel/>

Although tigecycline is one of the first lines of defense against carbapenemase-producing isolates, negative clinical outcomes with tigecycline have occurred. Both urinary tract and primary blood infections can make tigecycline ineffective, because it has limited penetration and rapid tissue diffusion after being intravenously infused, respectively.<ref name="Joel and Dallas review article">{{Cite journal |last=Kanj |first=Souha |last2=Zeina A. Kanafani |date=March 2011 |title=Current Concepts in Antimicrobial Therapy Against Resistant Gram-Negative Organisms: Extended-Spectrum β-lactamase-Producing Enterobacteriaceae, Carbapenem-Resistant Enterobacteriaceae, and Multidrug-Resistant Pseudomonas aeruginosa |journal=Mayo Clinic Proceedings |volume=86 |issue=3 |pages=250–259 |doi=10.4065/mcp.2010.0674 |pmc=3046948 |pmid=21364117}}</ref>

===Other antibiotics===
[[File:Nitrofurantoin 3D spacefill.png|thumb|right|350px|Nitrofurantoin ]]
Alternatives to fosfomycin include [[nitrofurantoin]], [[pivmecillinam]], and co-amoxiclav in oral treatment of urinary-tract infections associated with extended-spectrum beta-lactamase.<ref name="Fosfomycin" />

In a separate study, CRE were treated with [[colistin]], [[amikacin]], and tigecycline, and emphasizes the importance of using [[gentamicin]] in patients undergoing chemotherapy or stem-cell therapy procedures.While colistin had shown promising activity against carbapenemase-producing isolates, more recent data suggest a resistance to it is already emerging and it will soon become ineffective.<ref name="Joel and Dallas review article" />{{clarification needed}}

Using another antibiotic concomitantly with carbapenem can help prevent the development of carbapenem resistance. One specific study showed a higher rate of carbapenem resistance when using meropenem alone compared with combination therapy with moxifloxacin.<ref name="Bro005">{{Cite journal |last=Brunkhorst |first=Frank |last2=Oppert |first2=M |last3=Marx |first3=G |last4=Bloos |first4=F |last5=Ludewig |first5=K |last6=Putensen |first6=C |last7=Nierhaus |first7=A |last8=Jaschinski |first8=U |last9=Meier-Hellmann |first9=A |last10=Weyland |first10=A |last11=Gründling |first11=M |last12=Moerer |first12=O |last13=Riessen |first13=R |last14=Seibel |first14=A |last15=Ragaller |first15=M |display-authors=8 |date=13 June 2012 |title=Effect of Empirical Treatment With oxifloxacin and Meropenem vs Meropenem on Sepsis-Related Organ Dysfunction in Patients With Severe Sepsis: A Randomized Trial |journal=Journal of the American Medical Association |volume=307 |issue=22 |pages=2390–9 |doi=10.1001/jama.2012.5833 |pmid=22692171 |doi-access=free |last16=Büchler |first16=M. W. |last17=John |first17=S |last18=Bach |first18=F |last19=Spies |first19=C |last20=Reill |first20=L |last21=Fritz |first21=H |last22=Kiehntopf |first22=M |last23=Kuhnt |first23=E |last24=Bogatsch |first24=H |last25=Engel |first25=C |last26=Loeffler |first26=M |last27=Kollef |first27=M. H. |last28=Reinhart |first28=K |last29=Welte |first29=T |author30=German Study Group Competence Network Sepsis (SepNet)}}</ref>

In addition, several drugs were tested to gauge their effectiveness against CRE infections. ''In vitro'' studies have shown that [[rifampin]] has synergistic activity against carbapenem-resistant ''E. coli'' and ''K. pneumoniae''. However, more data are needed to determine if rifampin is effective in a clinical setting.<ref name="Joel and Dallas review article" />

Several new agents are in development. The main areas where scientists are focusing is new β-lactamase inhibitors with activity against carbapenemases. Some of these include MK-7655, NXL104, and 6-alkylidenepenam sulfones. The exact way they affect the carbapenemases is unknown. Another experimental agent with activity against CRE is [[eravacycline]].<ref name="Joel and Dallas review article" />

==Epidemiology==
[[File:PMC3744663 MEHD-23-11609-g004.png|thumb|right|450px| Prevalence of carbapenem-resistant Enterobacteriaceae from 10 areas in Zhejiang Province from 2000 to 2009<ref>{{Cite journal |last=Zhang |first=Rong |last2=Ichijo |first2=Tomoaki |last3=Hu |first3=Yan-Yan |last4=Zhou |first4=Hong-Wei |last5=Yamaguchi |first5=Nobuyasu |last6=Nasu |first6=Masao |last7=Chen |first7=Gong-Xiang |date=23 March 2012 |title=A ten years (2000–2009) surveillance of resistant Enterobacteriaceae in Zhejiang Province, China |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3744663/ |journal=Microbial Ecology in Health and Disease |volume=23 |pages=10.3402/mehd.v23i0.11609 |doi=10.3402/mehd.v23i0.11609 |issn=0891-060X |accessdate=6 September 2024}}</ref>

]]
Prior to 1992, CRE were relatively uncommon in the U.S. According to data from the National Nosocomial Infection Service, between 1986 and 1990, only 2.3% of 1825 Enterobacteriaceae isolates sampled were found to be resistant.<ref name="oxford" />

According to the U.S. Centers for Disease Control, CRE producing what was the most common type of carbapenem-destroying enzyme in 2001 were first detected in a North Carolina hospital in 1996.<ref>{{Cite journal |last=Yigit |first=H |last2=Queenan |first2=AM |last3=Anderson |first3=GJ |last4=Domenech-Sanchez |first4=A |last5=Biddle |first5=JW |last6=Steward |first6=CD |last7=Alberti |first7=S |last8=Bush |first8=K |last9=Tenover |first9=FC |date=April 2001 |title=Novel carbapenem-hydrolyzing beta-lactamase, KPC-1, from a carbapenem-resistant strain of ''Klebsiella pneumoniae'' |journal=Antimicrobial Agents and Chemotherapy |volume=45 |issue=4 |pages=1151–1161 |doi=10.1128/AAC.45.4.1151-1161.2001 |pmc=90438 |pmid=11257029}}</ref><ref name="Temkin2014">{{Cite journal |vauthors=Temkin E, Adler A, Lerner A, Carmeli Y |year=2014 |title=Carbapenem-resistant Enterobacteriaceae: biology, epidemiology, and management |url=https://www.openaccessrepository.it/record/21450 |url-status=live |journal=Annals of the New York Academy of Sciences |volume=1323 |issue=1 |pages=22–42 |bibcode=2014NYASA1323...22T |doi=10.1111/nyas.12537 |pmid=25195939 |s2cid=28242426 |archive-url=https://web.archive.org/web/20221128085029/https://www.openaccessrepository.it/record/21450 |archive-date=2022-11-28 |access-date=2023-03-12}}</ref> Since then, they have been identified in health care facilities in 41 other states. In 2012, 3% of patients in Chicago-area ICUs carried CRE.<ref name="USAtoday">{{Cite web |last=Peter Eisler |date=November 29, 2012 |title=Deadly superbugs invade U.S. health care facilities |url=https://www.usatoday.com/story/news/nation/2012/11/29/bacteria-deadly-hospital-infection/1727667/ |url-status=live |archive-url=https://web.archive.org/web/20121130235719/http://www.usatoday.com/story/news/nation/2012/11/29/bacteria-deadly-hospital-infection/1727667/ |archive-date=November 30, 2012 |access-date=December 1, 2012 |publisher=USA Today}}</ref> The same data indicated a 30% colonization rate in long-term care facilities , where patients are not [[symptomatic]]. During just the first half of 2012, almost 200 hospitals and long-term acute care facilities treated at least one patient infected with these bacteria.<ref name="CDC03513" />{{clarification needed}}

CRE have become increasingly common in the US. The Meropenem Yearly Susceptibility Test Information Collection Program noted that resistance within ''K. pneumoniae'' alone increased from 0.6% in 2004 to 5.6% in 2008.<ref name="oxford" /> The first outbreak involving colistin-resistant, carbapenem-resistant ''K. pneumoniae'' (CRKP) in the U.S. was discovered in [[Detroit]], Michigan in 2009, involving three different healthcare institutions.<ref>{{Cite journal |last=Marchaim |first=D |last2=Chopra |first2=T |last3=Pogue |first3=JM |last4=Perez |first4=F |last5=Hujer |first5=AM |last6=Rudin |first6=S |last7=Endimiani |first7=A |last8=Navon-Venezia |first8=S |last9=Hothi |first9=J |last10=Slim |first10=J. |last11=Blunden |first11=C. |last12=Shango |first12=M. |last13=Lephart |first13=P. R. |last14=Salimnia |first14=H. |last15=Reid |first15=D. |display-authors=8 |year=2011 |title=Outbreak of colistin-resistant, carbapenem-resistant ''Klebsiella pneumoniae'' in metropolitan Detroit, Michigan |journal=Antimicrobial Agents and Chemotherapy |volume=55 |issue=2 |pages=593–9 |doi=10.1128/AAC.01020-10 |pmc=3028794 |pmid=21115786 |last16=Moshos |first16=J. |last17=Hafeez |first17=W. |last18=Bheemreddy |first18=S. |last19=Chen |first19=T.-Y. |last20=Dhar |first20=S. |last21=Bonomo |first21=R. A. |last22=Kaye |first22=K. S.}}</ref> In an active surveillance study in seven U.S. states over two years, the crude overall incidence of CRE was 2.93 per 100,000 population. Georgia and Maryland had a significantly higher than predicted incidence adjusted for age and race.<ref name=jama/>

Increases in CRE have not been limited to the US. By 2011, CRE was reported in at least 22 countries.<ref name="oxford" /> Between 2009 and 2012, 10 cases of CRE infections were documented in ICU patients in a Melbourne, Australia, hospital.<ref name="Down the drain">{{Cite journal |last=Kotsanas |first=Despina |last2=Wijesooriya |first2=WR |last3=Korman |first3=TM |last4=Gillespie |first4=EE |last5=Wright |first5=L |last6=Snook |first6=K |last7=Williams |first7=N |last8=Bell |first8=JM |last9=Li |first9=HY |last10=Stuart |first10=Rhonda L |display-authors=8 |date=18 March 2013 |title="Down the drain": carbapenem-resistant bacteria in intensive care unit patients and handwashing sinks |journal=Medical Journal of Australia |volume=198 |issue=5 |pages=267–269 |doi=10.5694/mja12.11757 |pmid=23496403 |doi-access=free}}</ref>

Some cases of CRE are associated with receipt of medical care in the US. Strains found in Israel had genetic similarity to strains from the US.<ref name="Down the drain" />
Hospital handwashing stations were found to be environmental reservoirs for CRE after screening all wet-area locations, including sinks, water fountains, and ice machines. The main reservoirs for CRE were the ICU sinks, and inappropriate cleaning methods accounted for transmission from sink to sink. The CRE strains in the sinks and the strains infecting the ICU patients were identical per genetic analysis. At-risk patients were being infected in the hospital setting.<ref name="Down the drain" />

<gallery mode="packed" widths="360px" heights="220">
File:Carbapenem-resistant enterobacteriaceae epidemiology.webp|Annual proportions of carbapenemase producers (Klebsiella pneumoniae carbapenemase, oxacillinsase-48-like) between 2012 and 2017 - Taiwan<ref>{{Cite journal |last=Jean |first=Shio-Shin |last2=Lee |first2=Nan-Yao |last3=Tang |first3=Hung-Jen |last4=Lu |first4=Min-Chi |last5=Ko |first5=Wen-Chien |last6=Hsueh |first6=Po-Ren |date=27 November 2018 |title=Carbapenem-Resistant Enterobacteriaceae Infections: Taiwan Aspects |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277544/ |url-status=live |journal=Frontiers in Microbiology |volume=9 |pages=2888 |doi=10.3389/fmicb.2018.02888 |issn=1664-302X |archive-url=https://web.archive.org/web/20240914005357/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277544/ |archive-date=14 September 2024 |accessdate=12 September 2024}}</ref>

File:JLP-11-111-g002.jpg| Incidence of carbapenem-resistant ''Enterobacteriaceae'' by location;carbapenem-resistant ''Enterobacteriaceae'' cases per 10,000 <ref>{{Cite journal |last=Saeed |first=Nermin Kamal |last2=Alkhawaja |first2=Safaa |last3=Azam |first3=Nashawa Fawzy Abd El Moez |last4=Alaradi |first4=Khalil |last5=Al-Biltagi |first5=Mohammed |date=2019 |title=Epidemiology of carbapenem-resistant Enterobacteriaceae in a Tertiary Care Center in the Kingdom of Bahrain |url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543944/ |url-status=live |journal=Journal of Laboratory Physicians |volume=11 |issue=2 |pages=111–117 |doi=10.4103/JLP.JLP_101_18 |issn=0974-2727 |archive-url=https://web.archive.org/web/20240914005303/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543944/ |archive-date=2024-09-14 |access-date=2024-09-11}}</ref>
</gallery>
===Mortality===
CRE resistance depends upon a number of factors such as the health of the patient, whether the patient has recently undergone a transplant, risk of co-infection, and use of multiple antibiotics.<ref>{{Cite journal |last=Bonomo |first=RA |last2=van Duin |first2=D |last3=Kaye |first3=KS |last4=Neuner |first4=EA |year=2013 |title=Carbapenem-resistant Enterobacteriaceae: a review of treatment and outcomes |journal=Diagnostic Microbiology and Infectious Disease |volume=75 |issue=2 |pages=115–120 |doi=10.1016/j.diagmicrobio.2012.11.009 |pmc=3947910 |pmid=23290507}}</ref>
Carbapenem [[minimal inhibitory concentration]]s (MICs) results may be more predictive of clinical patient outcomes than the current categorical classification of the MICs being listed as susceptible, intermediate, or resistant.<ref name="NW">{{Cite journal |last=Esterly |first=JS |last2=Wagner |first2=J |last3=McLaughlin |first3=MM |last4=Postelnick |first4=MJ |last5=Qi |first5=C |last6=Scheetz |first6=MH |year=2012 |title=Evaluation of Clinical Outcomes in Patients with Bloodstream Infections Due to Gram-Negative Bacteria According to Carbapenem MIC Stratification |journal=Antimicrobial Agents and Chemotherapy |volume=56 |issue=9 |pages=4885–4890 |doi=10.1128/AAC.06365-11 |pmc=3421845 |pmid=22777044}}</ref> The study aimed to define an all-cause hospital mortality breakpoint for carbapenem MICs that were adjusted for risk factors. Another objective was to determine if a similar breakpoint existed for indirect outcomes, such as the time to death and length of stay after infection for survivors. Seventy-one patients were included, of which 52 patients survived and 19 patients died. Classification and regression tree analysis determined a split of organism MIC between 2 and 4&nbsp;mg/liter and predicted differences in mortality. In [[logistic regression]] controlling for confounders, each imipenem MIC doubling dilution doubled the probability of death. This classification scheme correctly predicted 82.6% of cases. Patients were accordingly stratified to MICs of ≤2&nbsp;mg/liter and ≥4&nbsp;mg/liter . Patients in the group with a MIC of ≥4&nbsp;mg/liter tended to be more ill. Secondary outcomes were also similar between groups. Patients with organisms that had an MIC of ≥4&nbsp;mg/liter had worse outcomes than those with isolates of an MIC of ≤2&nbsp;mg/liter.<ref name=NW/>

At [[New York Presbyterian Hospital]], part of [[Columbia University Medical Center]] in New York, NY, a study was conducted on the significant rise in carbapenem resistance in ''K. pneumoniae'' from 1999 to 2007. Following a positive blood culture from a patient, overall mortality was 23% in 7 days, 42% in 30 days, and 60% by the end of hospitalization. The overall in-hospital mortality rate was 48%.<ref name="Columbia University">{{Cite journal |last=Nguyen |first=M |last2=Eschenauer, GA |last3=Bryan, M |last4=O'Neil, K |last5=Furuya, EY |last6=Della-Latta, P |last7=Kubin, CJ |date=June 2010 |title=Carbapenem-resistant ''Klebsiella pneumoniae'' bacteremia: factors correlated with clinical and microbiologic outcomes |journal=Diagnostic Microbiology and Infectious Disease |volume=67 |issue=2 |pages=180–4 |doi=10.1016/j.diagmicrobio.2010.02.001 |pmid=20356699}}</ref>

At [[Soroka Medical Center]], an Israeli university teaching hospital, a study was done between October 2005 and October 2008 to determine the direct mortality rate associated with carbapenem-resistant ''K. pneumoniae'' bloodstream infections. The crude mortality rate for those with the resistant [[bacteremia]] was 71.9%, and the attributable mortality rate was determined to be 50% with a 95% confidence interval. The crude mortality rate for control subjects was 21.9%. As a result of the study, Soroka Medical Center started an intensive program designed to prevent the spread of carbapenem-resistant ''K. pneumoniae.''<ref name="soroka study">{{Cite journal |last=Borer |first=A |last2=Saidel-Odes, L |last3=Riesenberg, K |last4=Eskira, S |last5=Peled, N |last6=Nativ, R |last7=Schlaeffer, F |last8=Sherf, M |date=October 2009 |title=Attributable mortality rate for carbapenem-resistant ''Klebsiella pneumoniae'' bacteremia |journal=Infection Control and Hospital Epidemiology |volume=30 |issue=10 |pages=972–6 |doi=10.1086/605922 |pmid=19712030 |s2cid=33001455}}</ref>

A 2013 retrospective study at the Shaare Zedek Medical Center of patients with urinary tract infections (bacteriuria) caused by carbapenem-resistant [[Klebsiella pneumoniae|''Klebsiella pneumoniae'' (CRKp)]] showed no statistically significant difference in mortality rates from patients with bacteriuria caused by carbapenem-susceptible ''K. pneumoniae'' (CSKp). A 29% mortality rate was seen in patients with CRKp infection compared to a 25% mortality rate in patients with CSKp infections that produced extended-spectrum beta-lactamase (ESBL). Both mortality rates were considerably higher than that of patients with drug-susceptible [[urosepsis]].<ref name="Shilo et al., 2013">{{Cite journal |last=Shilo |first=S |last2=Assous |first2=MV |last3=Lachish |first3=T |last4=Kopuit |first4=P |last5=Bdolah-Abram |first5=T |last6=Yinnon |first6=AM |last7=Wiener-Well |first7=Y |year=2013 |title=Risk factors for bacteriuria with carbapenem-resistant Klebsiella pneumoniae and its impact on mortality: A case-control study |journal=Infection |volume=41 |issue=2 |pages=503–9 |doi=10.1007/s15010-012-0380-0 |pmid=23271210 |s2cid=10515716}}</ref> Most patients in the study had other illnesses, including [[dementia]], [[immunodeficiency|immune compromise]], [[kidney failure]], or [[diabetes mellitus]]. The main risk factor for death found by the study was being bedridden, which significantly increased the chance of death. This suggests that the deaths were due to reasons other than bacteriuria. Total length of hospitalization was somewhat longer in patients with CRKp infections .<ref name="Shilo et al., 2013" />

In a case-control study of 99 patients compared with 99 controls at [[Mount Sinai Hospital (Manhattan)]], a 1,171 bed tertiary care teaching hospital, 38% of patients in long-term care that were affected by CRE died from ''K. pneumoniae'' infection. Patients had risk factors including diabetes, HIV infection, heart disease, liver disease, [[chronic kidney disease]], one was a transplant recipient. 72% of patients who were released from the hospital with CRE were readmitted within 90 days.<ref>{{Cite journal |last=Calfee |first=DP |last2=Patel |first2=G |last3=Huprikar |first3=S |last4=Factor |first4=SH |last5=Jenkins |first5=SG |year=2008 |title=Outcomes of carbapenem-resistant ''Klebsiella pneumoniae'' infection and the impact of antimicrobial and adjunctive therapies |journal=Infection Control and Hospital Epidemiology |volume=29 |issue=12 |pages=1099–1106 |doi=10.1086/592412 |pmid=18973455 |s2cid=23992125}}</ref>
A 2008 study at Mount Sinai identified outcomes associated with Carbapenem-resistant ''Klebsiella pneumoniae'' infections, in which patients in need of organ or stem cell transplants, mechanical ventilation, prolonged hospitalization, or prior treatment with carbapenems, had an increased probability of infection with Carbapenem-resistant ''K. pneumoniae''. A combination of antibiotics worked to treat infection and survival rates of infected patients increased when the focus of infection was removed.<ref name="Patel et al. 2008">{{Cite journal |last=Patel |first=Gopi |last2=Huprikar |first2=S |last3=Factor |first3=SH |last4=Jenkins |first4=SG |last5=Calfee |first5=DP |date=December 2008 |title=Outcomes of Carbapenem-Resistant ''Klebsiella pneumoniae'' Infection and the Impact of Antimicrobial and Adjunctive Therapies |journal=Infection Control & Hospital Epidemiology |volume=29 |issue=12 |pages=1099–1106 |doi=10.1086/592412 |pmid=18973455 |s2cid=23992125}}</ref>

==Research==
===Public health implications===

Studies have found prolonged viability of bacteria on stainless-steel surfaces at room temperature. In a specific study, stainless steel was inoculated with 10<sup>7</sup> CFU/cm<sup>2</sup> ''E. coli'' and ''K. pneumonia'', containing bla<sub>CTX-M-15</sub> and bla<sub>NDM-1</sub> (antibiotic-resistant genes) respectively. Thirty days later (at room temperature, 22˚ C), 10<sup>4</sup> viable cells remained; and, after 100 days, 100 CFU/cm<sup>2</sup> of ''E. coli'' remained.<ref name="Public Health and Copper">{{Cite journal |last=Warnes |first=Sarah L. |last2=Highmore |first2=C. J. |last3=Keevil |first3=C. W. |date=November 27, 2012 |title=Horizontal Transfer of Antibiotic Resistance Genes on Abiotic Touch Surfaces: Implications for Public Health |journal=mBio |volume=3 |issue=6 |pages=e00489–12 |doi=10.1128/mBio.00489-12 |pmc=3509412 |pmid=23188508}}</ref>

In contrast, on [[copper]] and copper alloy surfaces, rapid death of antibiotic-resistant bacterial strains, as well as destruction of plasmid and genomic DNA, can be observed. Studies suggest that exposure to dry copper surfaces inhibits the respiration and growth of producers by releasing copper ions.<ref name="Public Health and Copper" />

Increased horizontal gene transfer (HGT) is observed simultaneously with cell viability on stainless steel surfaces. HGT is one of the major factors responsible for creating antibiotic resistance in bacteria. This suggests that immediate decontamination of surfaces is important in preventing the spread of antibiotic resistance genes. It has also been shown that horizontal transfer of antibiotic-resistant β-lactamase genes does not occur on antimicrobial copper surfaces. As copper surfaces degrade naked DNA , copper surfaces would halt HGT.<ref name="Public Health and Copper" />

Horizontal gene transfer has been demonstrated to occur readily on dry surfaces such as stainless steel, but not on copper and copper alloy surfaces. The rate of bacterial death increased proportionally with the percentage of copper in the copper alloy surface. This can be very important in future clinical and community settings, as an increase in copper utilization in hospital room equipment could help to greatly reduce the spread of antibiotic-resistant infection and the horizontal gene transfer of this antibiotic resistance.<ref name="Public Health and Copper" />

==See also==
* [[Methicillin-resistant Staphylococcus aureus|Methicillin-resistant staph aureus (MRSA)]]
* ''[[Clostridium difficile (bacteria)|Clostridium difficile]]''
* [[NDM-1]]

==References==
{{reflist|30em}}

==Further reading==
* [https://www.cdc.gov/hai/organisms/cre/cre-toolkit/index.html 2012 CRE Toolkit - Guidance for Control of Carbapenem-resistant Enterobacteriaceae (CRE)] {{Webarchive|url=https://web.archive.org/web/20220118234226/https://www.cdc.gov/hai/organisms/cre/cre-toolkit/index.html |date=2022-01-18 }} CDC Healthcare-associated Infections, March 2013
* [https://legionellacontrol.com/legionella/carbapenemase-enterobacteriaceae-cpe-hospital/ Carbapenemase-producing Enterobacteriaceae (CPE) Affects Hospital Patients] {{Webarchive|url=https://web.archive.org/web/20230203225827/https://legionellacontrol.com/legionella/carbapenemase-enterobacteriaceae-cpe-hospital/ |date=2023-02-03 }} Manchester Royal Infirmary were discovered to have the superbug known as carbapenemase-producing enterobacteriaceae, known for short as CPE

[[Category:Antibiotic-resistant bacteria]]
[[Category:Enterobacteriaceae]]
[[Category:Healthcare-associated infections]]

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