Editing Beta-lactamase (section)

==Resistance in gram-negative bacteria==
{{cleanup section|reason=confusing mix of structural and functional classifications; need explanatory paragraph on what these classes are|date=September 2021}}
Among gram-negative bacteria, the emergence of resistance to extended-spectrum cephalosporins has been a major concern. It appeared initially in a limited number of bacterial species (''[[Enterobacter cloacae|E. cloacae]]'', ''[[Citrobacter freundii|C. freundii]]'', ''[[S. marcescens]]'', and ''[[P. aeruginosa]]'') that could mutate to hyperproduce their chromosomal class C β-lactamase. A few years later, resistance appeared in bacterial species not naturally producing AmpC enzymes (''[[K. pneumoniae]]'', ''[[Salmonella]]'' spp., ''[[Proteus mirabilis|P. mirabilis]]'') due to the production of TEM- or SHV-type ESBLs (extended spectrum beta lactamases). Characteristically, such resistance has included oxyimino- (for example [[ceftizoxime]], [[cefotaxime]], [[ceftriaxone]], and [[ceftazidime]], as well as the oxyimino-monobactam [[aztreonam]]), but not 7-alpha-methoxy-cephalosporins ([[cephamycins]]; in other words, [[cefoxitin]] and [[cefotetan]]); has been blocked by inhibitors such as [[clavulanate]], [[sulbactam]] or [[tazobactam]] and did not involve [[carbapenems]] and [[temocillin]]. Chromosomal-mediated AmpC β-lactamases represent a new threat, since they confer resistance to 7-alpha-methoxy-cephalosporins ([[cephamycins]]) such as [[cefoxitin]] or [[cefotetan]] but are not affected by commercially available β-lactamase inhibitors, and can, in strains with loss of outer membrane porins, provide resistance to carbapenems.<ref name="pmid11751104">{{cite journal | vauthors = Philippon A, Arlet G, Jacoby GA | title = Plasmid-determined AmpC-type beta-lactamases | journal = Antimicrobial Agents and Chemotherapy | volume = 46 | issue = 1 | pages = 1–11 | date = January 2002 | pmid = 11751104 | pmc = 126993 | doi = 10.1128/AAC.46.1.1-11.2002 }}</ref>

===Extended-spectrum beta-lactamase (ESBL)===
Members of this family commonly express β-lactamases (e.g., TEM-3, TEM-4,<ref>{{cite web | title = Ambler class A beta-lactamases: TEM | url = http://bldb.eu/BLDB.php?prot=A#TEM | work = Beta-Lactamase DataBase (BLDB | access-date = 11 February 2022 | archive-date = 11 February 2022 | archive-url = https://web.archive.org/web/20220211114053/http://bldb.eu/BLDB.php?prot=A#TEM | url-status = live }}</ref> and SHV-2 <ref>{{cite web | title = Ambler class A beta-lactamases: SHV | url = http://bldb.eu/BLDB.php?prot=A#SHV | work = Beta-Lactamase DataBase (BLDB) | access-date = 11 February 2022 | archive-date = 11 February 2022 | archive-url = https://web.archive.org/web/20220211114053/http://bldb.eu/BLDB.php?prot=A#SHV | url-status = live }}</ref>) which confer resistance to expanded-spectrum (extended-spectrum) cephalosporins. In the mid-1980s, this new group of enzymes, the extended-spectrum β-lactamases (ESBLs), was detected (first detected in 1979).<ref name="pmid314270">{{cite journal | vauthors = Sanders CC, Sanders WE | title = Emergence of resistance to cefamandole: possible role of cefoxitin-inducible beta-lactamases | journal = Antimicrobial Agents and Chemotherapy | volume = 15 | issue = 6 | pages = 792–797 | date = June 1979 | pmid = 314270 | pmc = 352760 | doi = 10.1128/AAC.15.6.792 }}</ref> The prevalence of ESBL-producing bacteria have been gradually increasing in acute care hospitals.<ref>{{cite journal | vauthors = Spadafino JT, Cohen B, Liu J, Larson E | title = Temporal trends and risk factors for extended-spectrum beta-lactamase-producing Escherichia coli in adults with catheter-associated urinary tract infections | journal = Antimicrobial Resistance and Infection Control | volume = 3 | issue = 1 | pages = 39 | year = 2014 | pmid = 25625011 | pmc = 4306238 | doi = 10.1186/s13756-014-0039-y | doi-access = free }}</ref> The prevalence in the general population varies between countries, e.g. approximately 6% in Germany<ref>{{cite journal | vauthors = Symanzik C, Hillenbrand J, Stasielowicz L, Greie JC, Friedrich AW, Pulz M, John SM, Esser J | title = Novel insights into pivotal risk factors for rectal carriage of extended-spectrum-β-lactamase-producing enterobacterales within the general population in Lower Saxony, Germany | journal = Journal of Applied Microbiology | date = December 2021 | volume = 132 | issue = 4 | pages = 3256–3264 | pmid = 34856042 | doi = 10.1111/jam.15399 | s2cid = 244854840 | url = https://research.rug.nl/en/publications/44470d41-0614-468c-8e02-f1e748aba302 }}</ref> and France,<ref>{{cite journal | vauthors = Nicolas-Chanoine MH, Gruson C, Bialek-Davenet S, Bertrand X, Thomas-Jean F, Bert F, Moyat M, Meiller E, Marcon E, Danchin N, Noussair L, Moreau R, Leflon-Guibout V | title = 10-Fold increase (2006-11) in the rate of healthy subjects with extended-spectrum β-lactamase-producing Escherichia coli faecal carriage in a Parisian check-up centre | journal = The Journal of Antimicrobial Chemotherapy | volume = 68 | issue = 3 | pages = 562–568 | date = March 2013 | pmid = 23143897 | doi = 10.1093/jac/dks429 }}</ref> 13% in Saudi Arabia,<ref>{{cite journal | vauthors = Kader AA, Kamath KA | title = Faecal carriage of extended-spectrum beta-lactamase-producing bacteria in the community | journal = Eastern Mediterranean Health Journal| volume = 15 | issue = 6 | pages = 1365–1370 | date = 2009 | pmid = 20218126 }}</ref> and 63% in Egypt.<ref>{{cite journal | vauthors = Valverde A, Grill F, Coque TM, Pintado V, Baquero F, Cantón R, Cobo J | title = High rate of intestinal colonization with extended-spectrum-beta-lactamase-producing organisms in household contacts of infected community patients | journal = Journal of Clinical Microbiology | volume = 46 | issue = 8 | pages = 2796–2799 | date = August 2008 | pmid = 18562591 | pmc=2519510 | doi = 10.1128/JCM.01008-08 }}</ref> ESBLs are beta-lactamases that hydrolyze extended-spectrum cephalosporins with an oxyimino side chain. These cephalosporins include [[cefotaxime]], [[ceftriaxone]], and [[ceftazidime]], as well as the oxyimino-monobactam [[aztreonam]]. Thus ESBLs confer [[Multiple drug resistance|multi-resistance]] to these antibiotics and related oxyimino-beta lactams. In typical circumstances, they derive from genes for TEM-1, TEM-2, or SHV-1 by mutations that alter the amino acid configuration around the active site of these β-lactamases. A broader set of β-lactam antibiotics are susceptible to hydrolysis by these enzymes. An increasing number of ESBLs not of TEM or SHV lineage have recently been described.<ref name="pmid9230382">{{cite journal | vauthors = Emery CL, Weymouth LA | title = Detection and clinical significance of extended-spectrum beta-lactamases in a tertiary-care medical center | journal = Journal of Clinical Microbiology | volume = 35 | issue = 8 | pages = 2061–2067 | date = August 1997 | pmid = 9230382 | pmc = 229903 | doi = 10.1128/JCM.35.8.2061-2067.1997 }}</ref> The ESBLs are frequently plasmid encoded. Plasmids responsible for ESBL production frequently carry genes encoding resistance to other drug classes (for example, aminoglycosides). Therefore, antibiotic options in the treatment of ESBL-producing organisms are extremely limited. [[Carbapenem]]s are the treatment of choice for serious infections due to ESBL-producing organisms, yet carbapenem-resistant (primarily [[ertapenem]]-resistant) isolates have recently been reported.<ref name="Grundmann_2010">{{cite journal | vauthors = Grundmann H, Livermore DM, Giske CG, Canton R, Rossolini GM, Campos J, Vatopoulos A, Gniadkowski M, Toth A, Pfeifer Y, Jarlier V, Carmeli Y | title = Carbapenem-non-susceptible Enterobacteriaceae in Europe: conclusions from a meeting of national experts | journal = Euro Surveillance | volume = 15 | issue = 46 | date = November 2010 | pmid = 21144429 | doi = 10.2807/ese.15.46.19711-en | doi-access = free | hdl = 10400.18/206 | hdl-access = free }}</ref> ESBL-producing organisms may appear susceptible to some extended-spectrum [[cephalosporin]]s. However, treatment with such antibiotics has been associated with high failure rates.{{Citation needed|date=December 2015}}

=== Types ===
{{Redirect|Amp resistance|resistance to antimicrobial peptides|AMP resistance}}
==== TEM beta-lactamases (class A) ====
TEM-1 is the most commonly encountered beta-lactamase in [[gram-negative bacteria]]. Up to 90% of ampicillin resistance in [[Escherichia coli|''E. coli'']] is due to the production of TEM-1.<ref name="pmid2193616">{{cite journal | vauthors = Cooksey R, Swenson J, Clark N, Gay E, Thornsberry C | title = Patterns and mechanisms of beta-lactam resistance among isolates of Escherichia coli from hospitals in the United States | journal = Antimicrobial Agents and Chemotherapy | volume = 34 | issue = 5 | pages = 739–45 | date = May 1990 | pmid = 2193616 | pmc = 171683 | doi = 10.1128/AAC.34.5.739 }}</ref> Also responsible for the ampicillin and penicillin resistance that is seen in ''[[H. influenzae]]'' and ''[[N. gonorrhoeae]]'' in increasing numbers. Although TEM-type beta-lactamases are most often found in ''[[Escherichia coli|E. coli]]'' and ''[[K. pneumoniae]]'', they are also found in other species of gram-negative bacteria with increasing frequency. The amino acid substitutions responsible for the [[#Extended-spectrum beta-lactamase (ESBL)|extended-spectrum beta lactamase (ESBL)]] phenotype cluster around the active site of the enzyme and change its configuration, allowing access to oxyimino-beta-lactam substrates. Opening the active site to beta-lactam substrates also typically enhances the susceptibility of the enzyme to β-lactamase inhibitors, such as clavulanic acid. Single amino acid substitutions at positions 104, 164, 238, and 240 produce the ESBL phenotype, but ESBLs with the broadest spectrum usually have more than a single amino acid substitution. Based upon different combinations of changes, currently 140 TEM-type enzymes have been described. TEM-10, TEM-12, and TEM-26 are among the most common in the United States.<ref name="pmid14576117">{{cite journal | vauthors = Paterson DL, Hujer KM, Hujer AM, Yeiser B, Bonomo MD, Rice LB, Bonomo RA | title = Extended-spectrum beta-lactamases in Klebsiella pneumoniae bloodstream isolates from seven countries: dominance and widespread prevalence of SHV- and CTX-M-type beta-lactamases | journal = Antimicrobial Agents and Chemotherapy | volume = 47 | issue = 11 | pages = 3554–60 | date = November 2003 | pmid = 14576117 | pmc = 253771 | doi = 10.1128/AAC.47.11.3554-3560.2003 }}</ref><ref name="pmid11585791">{{cite journal | vauthors = Bradford PA | title = Extended-spectrum beta-lactamases in the 21st century: characterization, epidemiology, and detection of this important resistance threat | journal = Clinical Microbiology Reviews | volume = 14 | issue = 4 | pages = 933–51, table of contents | date = October 2001 | pmid = 11585791 | pmc = 89009 | doi = 10.1128/CMR.14.4.933-951.2001 }}</ref><ref name="pmid15673804">{{cite journal | vauthors = Jacoby GA, Munoz-Price LS | title = The new beta-lactamases | journal = The New England Journal of Medicine | volume = 352 | issue = 4 | pages = 380–91 | date = January 2005 | pmid = 15673804 | doi = 10.1056/NEJMra041359 }}</ref> The term TEM comes from the name of the Athenian patient (Temoniera) from which the isolate was recovered in 1963.<ref>{{cite journal  | doi = 10.3201/eid2404.et2404 | title = Etymologia: TEM | year = 2018 | vauthors = Ruiz J | journal = Emerging Infectious Diseases | volume = 24 | issue = 4 | page = 709 | doi-access = free | pmc = 5875283 }}</ref>

====SHV beta-lactamases (class A)====
SHV-1 shares 68 percent of its amino acids with TEM-1 and has a similar overall structure. The SHV-1 beta-lactamase is most commonly found in ''[[K. pneumoniae]]'' and is responsible for up to 20% of the plasmid-mediated ampicillin resistance in this species. ESBLs in this family also have amino acid changes around the active site, most commonly at positions 238 or 238 and 240. More than 60 SHV varieties are known. SHV-5 and SHV-12 are among the most common.<ref name="pmid14576117"/> The initials stand for "sulfhydryl reagent variable".<ref>{{cite journal | vauthors = Liakopoulos A, Mevius D, Ceccarelli D | title = A Review of SHV Extended-Spectrum β-Lactamases: Neglected Yet Ubiquitous | journal = Frontiers in Microbiology | volume = 7 | pages = 1374 | date = 2016-09-05 | pmid = 27656166 | pmc = 5011133 | doi = 10.3389/fmicb.2016.01374 | doi-access = free }}</ref>

==== CTX-M beta-lactamases (class A) ====
These enzymes were named for their greater activity against [[cefotaxime]] than other oxyimino-beta-lactam substrates (e.g., [[ceftazidime]], [[ceftriaxone]], or [[cefepime]]). Rather than arising by mutation, they represent examples of plasmid acquisition of beta-lactamase genes normally found on the chromosome of ''[[Kluyvera]]'' species, a group of rarely pathogenic commensal organisms. These enzymes are not very closely related to TEM or SHV beta-lactamases in that they show only approximately 40% identity with these two commonly isolated beta-lactamases. More than 172<ref>{{cite journal | vauthors = Ramadan AA, Abdelaziz NA, Amin MA, Aziz RK | title = Novel blaCTX-M variants and genotype-phenotype correlations among clinical isolates of extended spectrum beta lactamase-producing Escherichia coli | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 4224 | date = March 2019 | pmid = 30862858 | pmc = 6414621 | doi = 10.1038/s41598-019-39730-0 | s2cid = 75136447 | bibcode = 2019NatSR...9.4224R }}</ref> CTX-M enzymes are currently known. Despite their name, a few are more active on [[ceftazidime]] than [[cefotaxime]]. They are widely described among species of [[Enterobacteriaceae]], mainly ''E. coli'' and ''K. pneumoniae''. Detected in the 1980s they have since the early 2000s spread and are the now the predominant ESBL type in the world. They are generally clustred into five groups based on sequencing homologies; CTX-M-1, CTX-M-2, CTX-M-8, CTX-M-9 and CTX-M-25.  CTX-M-15 (belonging to the CTX-M-1 cluster) is the most prevalent CTX-M-gene.<ref>{{Cite journal |last=Castanheira |first=Mariana |date=3 Sep 2021 |title=Extended-spectrum β-lactamases: an update on their characteristics, epidemiology and detection |journal=Journal of Antimicrobial Chemotherapy|volume=3 |issue=3 |pages=dlab092 |doi=10.1093/jacamr/dlab092 |pmid=34286272 |pmc=8284625 }}</ref> An example of beta-lactamase CTX-M-15, along with IS''Ecp1'', has been found to have transposed onto the chromosome of ''[[Klebsiella pneumoniae]]'' ATCC BAA-2146.<ref>{{cite journal | vauthors = Hudson CM, Bent ZW, Meagher RJ, Williams KP | title = Resistance determinants and mobile genetic elements of an NDM-1-encoding Klebsiella pneumoniae strain | journal = PLOS ONE | volume = 9 | issue = 6 | pages = e99209 | date = 7 June 2014 | pmid = 24905728 | pmc = 4048246 | doi = 10.1371/journal.pone.0099209 | doi-access = free | bibcode = 2014PLoSO...999209H }}</ref> The initials stand for "Cefotaxime-Munich".<ref>{{Cite journal | vauthors = Cantón R, González-Alba JM, Galán JC |date=2012 |title=CTX-M Enzymes: Origin and Diffusion |journal= Frontiers in Microbiology |volume=3 |page=110 |doi=10.3389/fmicb.2012.00110 |pmid=22485109 |pmc=3316993 |issn=1664-302X|doi-access=free }}</ref>

==== OXA beta-lactamases (class D) ====
OXA beta-lactamases were long recognized as a less common but also plasmid-mediated beta-lactamase variety that could hydrolyze [[oxacillin]] and related anti-staphylococcal penicillins. These beta-lactamases differ from the TEM and SHV enzymes in that they belong to molecular class D and functional group 2d. The OXA-type beta-lactamases confer resistance to [[ampicillin]] and [[cephalothin]] and are characterized by their high hydrolytic activity against [[oxacillin]] and [[cloxacillin]] and the fact that they are poorly inhibited by [[clavulanic acid]]. Amino acid substitutions in OXA enzymes can also give the ESBL phenotype. While most ESBLs have been found in ''[[Escherichia coli|E. coli]]'', ''[[K. pneumoniae]]'', and other [[Enterobacteriaceae]], the OXA-type ESBLs have been found mainly in ''[[P. aeruginosa]]''. OXA-type ESBLs have been found mainly in ''[[Pseudomonas aeruginosa]]'' isolates from Turkey and France. The OXA beta-lactamase family was originally created as a phenotypic rather than a genotypic group for a few beta-lactamases that had a specific hydrolysis profile. Therefore, there is as little as 20% sequence homology among some of the members of this family. However, recent additions to this family show some degree of homology to one or more of the existing members of the OXA beta-lactamase family. Some confer resistance predominantly to ceftazidime, but OXA-17 confers greater resistance to cefotaxime and cefepime than it does resistance to ceftazidime.

==== Others ====
Other plasmid-mediated ESBLs, such as PER, VEB, GES, and IBC beta-lactamases, have been described but are uncommon and have been found mainly in ''[[P. aeruginosa]]'' and at a limited number of geographic sites. PER-1 in isolates in Turkey, France, and Italy; VEB-1 and VEB-2 in strains from Southeast Asia; and GES-1, GES-2, and IBC-2 in isolates from South Africa, France, and Greece. PER-1 is also common in multiresistant acinetobacter species in Korea and Turkey. Some of these enzymes are found in Enterobacteriaceae as well, whereas other uncommon ESBLs (such as BES-1, IBC-1, SFO-1, and TLA-1) have been found only in Enterobacteriaceae.

====Treatment====
While ESBL-producing organisms were previously associated with hospitals and institutional care, these organisms are now increasingly found in the community. CTX-M-15-positive [[Escherichia coli|E. coli]] are a cause of community-acquired [[cystitis|urinary infections]] in the UK,<ref name="Woodford_2006">{{cite web |display-authors=etal |title=Molecular characterisation of ''Escherichia coli'' isolates producing CTX-M-15 extended-spectrum β-lactamase (ESBL) in the United Kingdom |url=http://www.hpa.org.uk/cfi/armrl/ARMRL_posters/Woodford%20ECCMID%202004%20poster.pdf |url-status=dead |archive-url=https://web.archive.org/web/20070615160527/http://www.hpa.org.uk/cfi/armrl/ARMRL_posters/Woodford%20ECCMID%202004%20poster.pdf |archive-date=15 June 2007 |access-date=2006-11-19 |publisher=Health Protection Agency |vauthors=Woodford N, Ward E, Kaufmann ME}}</ref> and tend to be resistant to all oral β-lactam antibiotics, as well as [[quinolone antibiotic|quinolones]] and [[sulfonamide (medicine)|sulfonamide]]s. Treatment options may include [[nitrofurantoin]], [[fosfomycin]], [[mecillinam]] and [[chloramphenicol]].  In desperation, once-daily [[ertapenem]] or [[gentamicin]] injections may also be used.

=== Inhibitor-resistant β-lactamases ===
Although the inhibitor-resistant β-lactamases are not ESBLs, they are often discussed with ESBLs because they are also derivatives of the classical TEM- or SHV-type enzymes. These enzymes were at first given the designation IRT for inhibitor-resistant TEM β-lactamase; however, all have subsequently been renamed with numerical TEM designations. There are at least 19 distinct inhibitor-resistant TEM β-lactamases. Inhibitor-resistant TEM β-lactamases have been found mainly in clinical isolates of ''[[Escherichia coli|E. coli]]'', but also some strains of ''[[K. pneumoniae]]'', ''[[Klebsiella oxytoca]]'', ''[[Proteus mirabilis|P. mirabilis]]'', and ''[[Citrobacter freundii]]''. Although the inhibitor-resistant TEM variants are resistant to inhibition by [[clavulanic acid]] and [[sulbactam]], thereby showing clinical resistance to the beta-lactam—lactamase inhibitor combinations of [[amoxicillin]]-[[clavulanate]] ([[co-amoxiclav]]), [[ticarcillin]]-[[clavulanate]] ([[co-ticarclav]]), and [[ampicillin/sulbactam]], they normally remain susceptible to inhibition by [[tazobactam]] and subsequently the combination of [[piperacillin/tazobactam]],{{Citation needed|reason=Reliable source needed for the tazobactam susceptibility, as source n°4 states otherwise|date=November 2014}} although resistance has been described. This is no longer a primarily European epidemiology, it is found in northern parts of America often and should be tested for with complex UTI's.<ref name="pmid11585791"/>

===AmpC-type β-lactamases (class C)===
AmpC type β-lactamases are commonly isolated from extended-spectrum cephalosporin-resistant gram-negative bacteria. AmpC β-lactamases (also termed class C or group 1) are typically encoded on the chromosome of many gram-negative bacteria including ''[[Citrobacter]]'', ''[[Serratia]]'' and ''[[Enterobacter]]'' species where its expression is usually [[Regulation of gene expression#Inducible vs. repressible systems|inducible]]; it may also occur on ''[[Escherichia coli]]'' but is not usually inducible, although it can be hyperexpressed. AmpC type β-lactamases may also be carried on plasmids.<ref name="pmid11751104"/> AmpC β-lactamases, in contrast to ESBLs, hydrolyse broad and extended-spectrum cephalosporins (cephamycins as well as to oxyimino-β-lactams) but are not typically inhibited by the β-lactamase inhibitors [[clavulanic acid]] and [[tazobactam]], whereas [[avibactam]] can maintain inhibitory activity against this class of β-lactamases.<ref>{{cite web |url=http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206494Orig1s000MedR.pdf |title=Clinical Review, NDA 206494, Ceftazidime-avibactam |publisher=Food and Drug Administration (FDA) |date=2015-02-18 |access-date=14 November 2023 |archive-date=28 February 2017 |archive-url=https://web.archive.org/web/20170228174712/http://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/206494Orig1s000MedR.pdf |url-status=live }}</ref> AmpC-type β-lactamase organisms are often clinically grouped through the acronym, "SPACE": ''[[Serratia]], [[Pseudomonas]]'' or ''[[Proteus bacteria|Proteus]], [[Acinetobacter]], [[Citrobacter]]'', and ''[[Enterobacter]]''.