Beta-lactamase
Encyclopedia
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s produced by some bacteria and are responsible for their resistance
Antibiotic resistance
Antibiotic resistance is a type of drug resistance where a microorganism is able to survive exposure to an antibiotic. While a spontaneous or induced genetic mutation in bacteria may confer resistance to antimicrobial drugs, genes that confer resistance can be transferred between bacteria in a...
to beta-lactam antibiotic
Beta-lactam antibiotic
β-Lactam antibiotics are a broad class of antibiotics, consisting of all antibiotic agents that contains a β-lactam nucleus in its molecular structure. This includes penicillin derivatives , cephalosporins , monobactams, and carbapenems...
s like penicillin
Penicillin
Penicillin is a group of antibiotics derived from Penicillium fungi. They include penicillin G, procaine penicillin, benzathine penicillin, and penicillin V....
s, cephamycin
Cephamycin
Cephamycins are a group of beta-lactam antibiotics. They are very similar to cephalosporins, and the cephamycins are sometimes classified as cephalosporins.Like cephalosporins, cephamycins are based upon the cephem nucleus...
s, and carbapenem
Carbapenem
Carbapenems are a class of β-lactam antibiotics with a broad spectrum of antibacterial activity. They have a structure that renders them highly resistant to most β-lactamases...
s (ertapenem
Ertapenem
Ertapenem is a carbapenem antibiotic marketed by Merck as Invanz. It is structurally very similar to meropenem in that it possess a 1-β-methyl group.-Indications:...
). (Cephalosporin
Cephalosporin
The cephalosporins are a class of β-lactam antibiotics originally derived from Acremonium, which was previously known as "Cephalosporium".Together with cephamycins they constitute a subgroup of β-lactam antibiotics called cephems.-Medical use:...
s are relatively resistant to beta-lactamase.) These antibiotic
Antibiotic
An antibacterial is a compound or substance that kills or slows down the growth of bacteria.The term is often used synonymously with the term antibiotic; today, however, with increased knowledge of the causative agents of various infectious diseases, antibiotic has come to denote a broader range of...
s have a common element in their molecular structure: a four-atom ring known as a beta-lactam
Beta-lactam
A β-lactam ring, is a four-membered lactam. It is named as such, because the nitrogen atom is attached to the β-carbon relative to the carbonyl...
. The lactamase enzyme breaks that ring open, deactivating the molecule's antibacterial properties.
Beta-lactam antibiotics are typically used to treat a broad spectrum of Gram-positive
Gram-positive
Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. This is in contrast to Gram-negative bacteria, which cannot retain the crystal violet stain, instead taking up the counterstain and appearing red or pink...
and Gram-negative
Gram-negative
Gram-negative bacteria are bacteria that do not retain crystal violet dye in the Gram staining protocol. In a Gram stain test, a counterstain is added after the crystal violet, coloring all Gram-negative bacteria with a red or pink color...
bacteria. Beta-lactamases produced by Gram-negative organisms are usually secreted.
The structure of a Streptomyces
Streptomyces
Streptomyces is the largest genus of Actinobacteria and the type genus of the family Streptomycetaceae. Over 500 species of Streptomyces bacteria have been described. As with the other Actinobacteria, streptomycetes are gram-positive, and have genomes with high guanine and cytosine content...
β lactamase is given by .
Penicillinase
Penicillinase is a specific type of β-lactamase, showing specificity for penicillinPenicillin
Penicillin is a group of antibiotics derived from Penicillium fungi. They include penicillin G, procaine penicillin, benzathine penicillin, and penicillin V....
s, again by hydrolysing
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
the beta-lactam
Beta-lactam
A β-lactam ring, is a four-membered lactam. It is named as such, because the nitrogen atom is attached to the β-carbon relative to the carbonyl...
ring. Molecular weights of the various penicillinases tend to cluster near 50 kiloDaltons.
Penicillinase was the first β-lactamase to be identified: It was first isolated by Abraham and Chain in 1940 from Gram-negative E. coli even before penicillin entered clinical use, but penicillinase production quickly spread to bacteria that previously did not produce it or produced it only rarely. Penicillinase-resistant beta-lactams such as methicillin
Methicillin
Meticillin or methicillin is a narrow-spectrum beta-lactam antibiotic of the penicillin class. It should not be confused with the antibiotic metacycline.-History:Methicillin was developed by Beecham in 1959...
were developed, but there is now widespread resistance
Antibiotic resistance
Antibiotic resistance is a type of drug resistance where a microorganism is able to survive exposure to an antibiotic. While a spontaneous or induced genetic mutation in bacteria may confer resistance to antimicrobial drugs, genes that confer resistance can be transferred between bacteria in a...
to even these.
Group 1
CEPHALOSPORINASE, Molecular Class C (not inhibited by clavulanic acid)- Group 1 are cephalosporinases not inhibited by clavulanic acidClavulanic acidClavulanic acid is a competitive β-lactamase inhibitor combined with penicillin group antibiotics to overcome certain types of antibiotic resistance. It is used to overcome resistance in bacteria that secrete β-lactamase, which otherwise inactivates most penicillins...
, belonging to the molecular class C
Group 2
Group 2 are penicillinases, cephalosporinases, or both inhibited by clavulanic acid, corresponding to the molecular classes A and D reflecting the original TEM and SHV genes. However, because of the increasing number of TEM- and SHV-derived β-lactamases, they were divided into two subclasses, 2a and 2b.GROUP 2a: PENICILLINASE, Molecular Class A
- The 2a subgroup contains just penicillinases.
GROUP 2b: BROAD-SPECTRUM, Molecular Class A
- 2b Opposite to 2a , 2b are broad-spectrum β-lactamases, meaning that they are capable of inactivating penicillins and cephalosporins at the same rate. Furthermore, new subgroups were segregated from subgroup 2b:
GROUP 2be: EXTENDED-SPECTRUM, Molecular Class A
- Subgroup 2be, with the letter "e" for extended spectrum of activity, represents the ESBLs, which are capable of inactivating third-generation cephalosporins (ceftazidimeCeftazidimeCeftazidime is a third-generation cephalosporin antibiotic. Like other third-generation cephalosporins, it has broad spectrum activity against Gram-positive and Gram-negative bacteria. Unlike most third-generation agents, it is active against Pseudomonas aeruginosa, however it has weaker activity...
, cefotaximeCefotaximeCefotaxime is a third-generation cephalosporin antibiotic. Like other third-generation cephalosporins, it has broad spectrum activity against Gram positive and Gram negative bacteria...
, and cefpodoximeCefpodoximeCefpodoxime is an oral third generation cephalosporin antibiotic. It is marketed as the prodrug cefpodoxime proxetil by Pharmacia & Upjohn under the trade name Vantin. It is active against most Gram positive and Gram negative organisms. Notable exceptions include Pseudomonas aeruginosa,...
) as well as monobactamsMonobactamsMonobactams are β-lactam compounds wherein the β-lactam ring is alone and not fused to another ring...
(aztreonam)
GROUP 2br: INHIBITOR-RESISTANT, Molecular Class A (diminished inhibition by clavulanic acid)
- The 2br enzymes, with the letter "r" denoting reduced binding to clavulanic acidClavulanic acidClavulanic acid is a competitive β-lactamase inhibitor combined with penicillin group antibiotics to overcome certain types of antibiotic resistance. It is used to overcome resistance in bacteria that secrete β-lactamase, which otherwise inactivates most penicillins...
and sulbactamSulbactamSulbactam is a molecule that is given in combination with beta-lactam antibiotics to inhibit beta-lactamase, an enzyme produced by bacteria that destroys the antibiotics...
, are also called inhibitor-resistant TEM-derivative enzymes; nevertheless, they are commonly still susceptible to tazobactamTazobactamTazobactam is a compound that inhibits the action of bacterial beta-lactamases. It is added to the extended spectrum beta-lactam antibiotic piperacillin to produce Tazocin or Zosyn or Piprataz...
, except where an amino acid replacement exists at position met69.
GROUP 2c: CARBENICILLINASE, Molecular Class A
- Latersubgroup 2c was segregated from group 2 because these enzymes inactivate carbenicillinCarbenicillinCarbenicillin is a bacteriolytic antibiotic belonging to the carboxypenicillin subgroup of the penicillins. It was discovered by scientists at Beecham and marketed as Pyopen. It has Gram-negative coverage which includes Pseudomonas aeruginosa but limited Gram-positive coverage...
more than benzylpenicillinBenzylpenicillinBenzylpenicillin, commonly known as penicillin G, is the gold standard type of penicillin. 'G' in the name 'Penicillin G' refers to 'Gold Standard'. Penicillin G is typically given by a parenteral route of administration because it is unstable in the hydrochloric acid of the stomach...
, with some effect on cloxacillinCloxacillinCloxacillin is a semisynthetic antibiotic in the same class as penicillin. Cloxacillin was discovered and developed by Beecham. It is sold under a number of trade names, including Cloxapen, Cloxacap, Tegopen and Orbenin....
.
GROUP 2d: CLOXACILANASE, Molecular Class D or A
- Subgroup 2d enzymes inactivate cloxacillinCloxacillinCloxacillin is a semisynthetic antibiotic in the same class as penicillin. Cloxacillin was discovered and developed by Beecham. It is sold under a number of trade names, including Cloxapen, Cloxacap, Tegopen and Orbenin....
more than benzylpenicillinBenzylpenicillinBenzylpenicillin, commonly known as penicillin G, is the gold standard type of penicillin. 'G' in the name 'Penicillin G' refers to 'Gold Standard'. Penicillin G is typically given by a parenteral route of administration because it is unstable in the hydrochloric acid of the stomach...
, with some activity against carbenicillinCarbenicillinCarbenicillin is a bacteriolytic antibiotic belonging to the carboxypenicillin subgroup of the penicillins. It was discovered by scientists at Beecham and marketed as Pyopen. It has Gram-negative coverage which includes Pseudomonas aeruginosa but limited Gram-positive coverage...
; these enzymes are poorly inhibited by clavulanic acidClavulanic acidClavulanic acid is a competitive β-lactamase inhibitor combined with penicillin group antibiotics to overcome certain types of antibiotic resistance. It is used to overcome resistance in bacteria that secrete β-lactamase, which otherwise inactivates most penicillins...
, and some of them are ESBLs
- the correct term is "OXACILLINASE". These enzymes are able to inactivate the oxazolylpenicillins like oxacillin, cloxacillin, dicloxacillin. The enzymes belong to the molecular class D not molecular class A.
GROUP 2e: CEPHALOSPORINASE, Molecular Class A
- Subgroup 2e enzymes are cephalosporinases that can also hydrolyse monobactamsMonobactamsMonobactams are β-lactam compounds wherein the β-lactam ring is alone and not fused to another ring...
, and they are inhibited by clavulanic acidClavulanic acidClavulanic acid is a competitive β-lactamase inhibitor combined with penicillin group antibiotics to overcome certain types of antibiotic resistance. It is used to overcome resistance in bacteria that secrete β-lactamase, which otherwise inactivates most penicillins...
GROUP 2f: CARBAPENAMASE, Molecular Class A
- Subgroup 2f was added because these are serineSerineSerine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
-based carbapenemases, in contrast to the zinc-based carbapenemases included in group 3
Group 3
METALLOENZYME, Molecular Class B (not inhibited by clavulanic acid)- Group 3 are the zincZincZinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...
-based or metallo {beta}-lactamases, corresponding to the molecular class B, which are the only enzymes acting by the metal ion zinc, as discussed above. Metallo B-lactamases are able to hydrolyse penicillins, cephalosporins, and carbapenems. Thus, carbapenems are inhibited by both group 2f (serine-based mechanism) and group 3 (zinc-based mechanism)
Group 4
PENICILLINASE, No Molecular Class (not inhibited by clavulanic acid)- Group 4 are penicillinases that are not inhibited by clavulanic acidClavulanic acidClavulanic acid is a competitive β-lactamase inhibitor combined with penicillin group antibiotics to overcome certain types of antibiotic resistance. It is used to overcome resistance in bacteria that secrete β-lactamase, which otherwise inactivates most penicillins...
, and they do not yet have a corresponding molecular class.
Molecular Classification
The molecular classification of β-lactamases is based on the nucleotide and amino acid sequences in these enzymes. To date, four classes are recognised (A-D), correlating with the functional classification. Classes A, C, and D act by a serineSerine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
-based mechanism, whereas class B or metallo-β-lactamases
Metallo-beta-lactamase protein fold
The metallo-beta-lactamase protein fold is a protein domain contained in class B beta-lactamases and a number of other proteins.These proteins include thiolesterases, members of the glyoxalase II family, that catalyse the hydrolysis of S-D-lactoyl-glutathione to form glutathione and D-lactic acid...
need zinc
Zinc
Zinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...
for their action
"Penicillinase" was discovered in 1940 and re-named Beta-lactamase when the structure of the Beta-lactam ring was finally elucidated.
Resistance in Gram-negative bacteria
Among Gram-negative bacteria, the emergence of resistance to expanded-spectrum cephalosporins has been a major concern. It appeared initially in a limited number of bacterial species (E. cloacae, 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, SalmonellaSalmonella
Salmonella is a genus of rod-shaped, Gram-negative, non-spore-forming, predominantly motile enterobacteria with diameters around 0.7 to 1.5 µm, lengths from 2 to 5 µm, and flagella which grade in all directions . They are chemoorganotrophs, obtaining their energy from oxidation and reduction...
spp., P. mirabilis
Proteus mirabilis
Proteus mirabilis is a Gram-negative, facultatively anaerobic, rod shaped bacterium. It shows swarming motility, and urease activity. P. mirabilis causes 90% of all Proteus infections in humans.-Diagnosis:...
) due to the production of TEM- or SHV-type ESBLs. Characteristically, such resistance has included oxyimino- (for example ceftizoxime
Ceftizoxime
Ceftizoxime is a parenteral third-generation cephalosporin.Unlike other 3rd generation cephalosporins , in ceftizoxime the whole C-3 side chain has been removed to prevent deactivation by hydrolytic enzymes ....
, cefotaxime
Cefotaxime
Cefotaxime is a third-generation cephalosporin antibiotic. Like other third-generation cephalosporins, it has broad spectrum activity against Gram positive and Gram negative bacteria...
, ceftriaxone
Ceftriaxone
Ceftriaxone is a third-generation cephalosporin antibiotic. Like other third-generation cephalosporins, it has broad spectrum activity against Gram-positive and Gram-negative bacteria. In most cases, it is considered to be equivalent to cefotaxime in terms of safety and efficacy...
, and ceftazidime
Ceftazidime
Ceftazidime is a third-generation cephalosporin antibiotic. Like other third-generation cephalosporins, it has broad spectrum activity against Gram-positive and Gram-negative bacteria. Unlike most third-generation agents, it is active against Pseudomonas aeruginosa, however it has weaker activity...
, as well as the oxyimino-monobactam aztreonam
Aztreonam
Aztreonam is a synthetic monocyclic beta-lactam antibiotic , with the nucleus based on a simpler monobactam isolated from Chromobacterium violaceum. It was approved by the U.S. Food and Drug Administration in 1986...
), but not 7-alpha-methoxy-cephalosporins (cephamycins); in other words, (cefoxitin
Cefoxitin
Cefoxitin is a cephamycin antibiotic developed by Merck & Co., Inc., often grouped with the second−generation cephalosporins. It is sold under the brand name Mefoxin.- Microbiology :...
and cefotetan
Cefotetan
Cefotetan is an injectable antibiotic of the cephamycin type for prophylaxis and treatment of bacterial infections. It is often grouped together with second-generation cephalosporins and has a similar antibacterial spectrum, but with additional anti-anaerobe coverage.Cefotetan was developed by...
) have been blocked by inhibitors such as clavulanate, sulbactam
Sulbactam
Sulbactam is a molecule that is given in combination with beta-lactam antibiotics to inhibit beta-lactamase, an enzyme produced by bacteria that destroys the antibiotics...
, or tazobactam
Tazobactam
Tazobactam is a compound that inhibits the action of bacterial beta-lactamases. It is added to the extended spectrum beta-lactam antibiotic piperacillin to produce Tazocin or Zosyn or Piprataz...
, and did not involve carbapenems. Chromosomal-mediated AmpC β-lactamases represent a new threat, since they confer resistance to 7-alpha-methoxy-cephalosporins (cephamycins) such as cefoxitin
Cefoxitin
Cefoxitin is a cephamycin antibiotic developed by Merck & Co., Inc., often grouped with the second−generation cephalosporins. It is sold under the brand name Mefoxin.- Microbiology :...
or cefotetan
Cefotetan
Cefotetan is an injectable antibiotic of the cephamycin type for prophylaxis and treatment of bacterial infections. It is often grouped together with second-generation cephalosporins and has a similar antibacterial spectrum, but with additional anti-anaerobe coverage.Cefotetan was developed by...
are not affected by commercially-available β-lactamase inhibitors, and can, in strains with loss of outer membrane porins, provide resistance to carbapenems.
Extended-spectrum beta-lactamase (ESBL)
Members of the family EnterobacteriaceaeEnterobacteriaceae
The Enterobacteriaceae is a large family of bacteria that includes many of the more familiar pathogens, such as Salmonella, Escherichia coli, Yersinia pestis, Klebsiella and Shigella. This family is the only representative in the order Enterobacteriales of the class Gammaproteobacteria in the...
commonly express plasmid-encoded β-lactamases (e.g., TEM-1, TEM-2, and SHV-1). which confer resistance to penicillins but not to expanded-spectrum cephalosporins. In the mid-1980s, a new group of enzymes, the extended-spectrum b-lactamases (ESBLs), was detected. (first detected in Germany in 1983). ESBLs are beta-lactamases that hydrolyze extended-spectrum cephalosporins with an oxyimino side chain. These cephalosporins include cefotaxime
Cefotaxime
Cefotaxime is a third-generation cephalosporin antibiotic. Like other third-generation cephalosporins, it has broad spectrum activity against Gram positive and Gram negative bacteria...
, ceftriaxone
Ceftriaxone
Ceftriaxone is a third-generation cephalosporin antibiotic. Like other third-generation cephalosporins, it has broad spectrum activity against Gram-positive and Gram-negative bacteria. In most cases, it is considered to be equivalent to cefotaxime in terms of safety and efficacy...
, and ceftazidime
Ceftazidime
Ceftazidime is a third-generation cephalosporin antibiotic. Like other third-generation cephalosporins, it has broad spectrum activity against Gram-positive and Gram-negative bacteria. Unlike most third-generation agents, it is active against Pseudomonas aeruginosa, however it has weaker activity...
, as well as the oxyimino-monobactam aztreonam
Aztreonam
Aztreonam is a synthetic monocyclic beta-lactam antibiotic , with the nucleus based on a simpler monobactam isolated from Chromobacterium violaceum. It was approved by the U.S. Food and Drug Administration in 1986...
. Thus ESBLs confer 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. This extends the spectrum of β-lactam antibiotics susceptible to hydrolysis by these enzymes. An increasing number of ESBLs not of TEM or SHV lineage have recently been described. 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. Carbapenems are the treatment of choice for serious infections due to ESBL-producing organisms, yet carbapenem-resistant isolates have recently been reported. ESBL-producing organisms may appear susceptible to some extended-spectrum cephalosporins. However, treatment with such antibiotics has been associated with high failure rates.
TEM beta-lactamases (class A)
TEM-1 is the most commonly-encountered beta-lactamase in Gram-negativeGram-negative
Gram-negative bacteria are bacteria that do not retain crystal violet dye in the Gram staining protocol. In a Gram stain test, a counterstain is added after the crystal violet, coloring all Gram-negative bacteria with a red or pink color...
bacteria. Up to 90% of ampicillin resistance in E. coli is due to the production of TEM-1. 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 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 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 b-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.
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. They are the predominant ESBL type in Europe and the United States and are found worldwide. SHV-5 and SHV-12 are among the most common.CTX-M beta-lactamases (class A)
These enzymes were named for their greater activity against cefotaximeCefotaxime
Cefotaxime is a third-generation cephalosporin antibiotic. Like other third-generation cephalosporins, it has broad spectrum activity against Gram positive and Gram negative bacteria...
than other oxyimino-beta-lactam substrates (e.g., ceftazidime
Ceftazidime
Ceftazidime is a third-generation cephalosporin antibiotic. Like other third-generation cephalosporins, it has broad spectrum activity against Gram-positive and Gram-negative bacteria. Unlike most third-generation agents, it is active against Pseudomonas aeruginosa, however it has weaker activity...
, ceftriaxone
Ceftriaxone
Ceftriaxone is a third-generation cephalosporin antibiotic. Like other third-generation cephalosporins, it has broad spectrum activity against Gram-positive and Gram-negative bacteria. In most cases, it is considered to be equivalent to cefotaxime in terms of safety and efficacy...
, or cefepime
Cefepime
Cefepime is a fourth-generation cephalosporin antibiotic developed in 1994. Cefepime has an extended spectrum of activity against Gram-positive and Gram-negative bacteria, with greater activity against both Gram-negative and Gram-positive organisms than third-generation agents...
). 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 80 CTX-M enzymes are currently known. Despite their name, a few are more active on ceftazidime
Ceftazidime
Ceftazidime is a third-generation cephalosporin antibiotic. Like other third-generation cephalosporins, it has broad spectrum activity against Gram-positive and Gram-negative bacteria. Unlike most third-generation agents, it is active against Pseudomonas aeruginosa, however it has weaker activity...
than cefotaxime
Cefotaxime
Cefotaxime is a third-generation cephalosporin antibiotic. Like other third-generation cephalosporins, it has broad spectrum activity against Gram positive and Gram negative bacteria...
. They have mainly been found in strains of Salmonella enterica
Salmonella enterica
Salmonella enterica is a rod-shaped flagellated, facultative anaerobic, Gram-negative bacterium, and a member of the genus Salmonella.- Epidemiology :...
serovar Typhimurium and E. coli, but have also been described in other species of Enterobacteriaceae
Enterobacteriaceae
The Enterobacteriaceae is a large family of bacteria that includes many of the more familiar pathogens, such as Salmonella, Escherichia coli, Yersinia pestis, Klebsiella and Shigella. This family is the only representative in the order Enterobacteriales of the class Gammaproteobacteria in the...
and are the predominant ESBL type in parts of South America. (They are also seen in eastern Europe) CTX-M-14, CTX-M-3, and CTX-M-2 are the most widespread. CTX-M-15 is currently (2006) the most widespread type in E. coli
Escherichia coli
Escherichia coli is a Gram-negative, rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms . Most E. coli strains are harmless, but some serotypes can cause serious food poisoning in humans, and are occasionally responsible for product recalls...
the UK and is widely prevalent in the community.
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 oxacillinOxacillin
Oxacillin sodium is a narrow spectrum beta-lactam antibiotic of the penicillin class.It was developed by Beecham.-Uses:...
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
Ampicillin
Ampicillin is a beta-lactam antibiotic that has been used extensively to treat bacterial infections since 1961. Until the introduction of ampicillin by the British company Beecham, penicillin therapies had only been effective against Gram-positive organisms such as staphylococci and streptococci...
and cephalothin and are characterized by their high hydrolytic activity against oxacillin
Oxacillin
Oxacillin sodium is a narrow spectrum beta-lactam antibiotic of the penicillin class.It was developed by Beecham.-Uses:...
and cloxacillin
Cloxacillin
Cloxacillin is a semisynthetic antibiotic in the same class as penicillin. Cloxacillin was discovered and developed by Beecham. It is sold under a number of trade names, including Cloxapen, Cloxacap, Tegopen and Orbenin....
and the fact that they are poorly inhibited by clavulanic acid
Clavulanic acid
Clavulanic acid is a competitive β-lactamase inhibitor combined with penicillin group antibiotics to overcome certain types of antibiotic resistance. It is used to overcome resistance in bacteria that secrete β-lactamase, which otherwise inactivates most penicillins...
. Amino acid substitutions in OXA enzymes can also give the ESBL phenotype. While most ESBLs have been found in E. coli, K. pneumoniae, and other Enterobacteriaceae
Enterobacteriaceae
The Enterobacteriaceae is a large family of bacteria that includes many of the more familiar pathogens, such as Salmonella, Escherichia coli, Yersinia pestis, Klebsiella and Shigella. This family is the only representative in the order Enterobacteriales of the class Gammaproteobacteria in the...
, the OXA-type ESBLs have been found mainly in P. aeruginosa. OXA-type ESBLs have been found mainly in Pseudomonas aeruginosa
Pseudomonas aeruginosa
Pseudomonas aeruginosa is a common bacterium that can cause disease in animals, including humans. It is found in soil, water, skin flora, and most man-made environments throughout the world. It thrives not only in normal atmospheres, but also in hypoxic atmospheres, and has, thus, colonized many...
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 E. coliEscherichia coli
Escherichia coli is a Gram-negative, rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms . Most E. coli strains are harmless, but some serotypes can cause serious food poisoning in humans, and are occasionally responsible for product recalls...
are a cause of community-acquired urinary infections
Cystitis
Cystitis is a term that refers to urinary bladder inflammation that results from any one of a number of distinct syndromes. It is most commonly caused by a bacterial infection in which case it is referred to as a urinary tract infection.-Signs and symptoms:...
in the UK, and tend to be resistant to all oral β-lactam antibiotics, as well as quinolones and sulfonamide
Sulfonamide (medicine)
Sulfonamide or sulphonamide is the basis of several groups of drugs. The original antibacterial sulfonamides are synthetic antimicrobial agents that contain the sulfonamide group. Some sulfonamides are also devoid of antibacterial activity, e.g., the anticonvulsant sultiame...
s. Treatment options may include nitrofurantoin
Nitrofurantoin
Nitrofurantoin is an antibiotic which is marketed under the following brand names; Furadantin, Macrobid, Macrodantin, Nitrofur Mac, Nitro Macro, Nifty-SR, Martifur-MR, Martifur-100 , Urantoin, and Uvamin . It is usually used in treating urinary tract infection...
, fosfomycin
Fosfomycin
Fosfomycin is a broad-spectrum antibiotic produced by certain Streptomyces species.-Uses:...
, mecillinam
Mecillinam
Mecillinam or amdinocillin , trade name Coactin, is an extended-spectrum penicillin antibiotic that binds specifically to penicillin binding protein 2 , and is only considered to be active against Gram-negative bacteria. It is used primarily in the treatment of urinary tract infections, and has...
and chloramphenicol
Chloramphenicol
Chloramphenicol is a bacteriostatic antimicrobial that became available in 1949. It is considered a prototypical broad-spectrum antibiotic, alongside the tetracyclines, and as it is both cheap and easy to manufacture it is frequently found as a drug of choice in the third world.Chloramphenicol is...
. In desperation, once-daily ertapenem
Ertapenem
Ertapenem is a carbapenem antibiotic marketed by Merck as Invanz. It is structurally very similar to meropenem in that it possess a 1-β-methyl group.-Indications:...
or gentamicin
Gentamicin
Gentamicin is an aminoglycoside antibiotic, used to treat many types of bacterial infections, particularly those caused by Gram-negative organisms. However, gentamicin is not used for Neisseria gonorrhoeae, Neisseria meningitidis or Legionella pneumophila...
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 E. coli, but also some strains of K. pneumoniae, Klebsiella oxytocaKlebsiella oxytoca
Klebsiella oxytoca is a Gram-negative, rod-shaped bacterium that is closely related to K. pneumoniae, from which it is distinguished by being indole-positive; it also has slightly different growth characteristics in that it is able to grow on melezitose, but not 3-hydroxybutyrate.- Industrial uses...
, P. mirabilis
Proteus mirabilis
Proteus mirabilis is a Gram-negative, facultatively anaerobic, rod shaped bacterium. It shows swarming motility, and urease activity. P. mirabilis causes 90% of all Proteus infections in humans.-Diagnosis:...
, and Citrobacter freundii
Citrobacter freundii
Citrobacter freundii are aerobic Gram-negative bacilli. The bacteria are long rod-shaped with a typically length of 1-5 μm. Most C. freundii cells are surrounded by several flagella used for locomotion, but a few are non-motile. It can be found in soil, water, sewage, food and the intestinal tracts...
.Although the inhibitor-resistant TEM variants are resistant to inhibition by clavulanic acid
Clavulanic acid
Clavulanic acid is a competitive β-lactamase inhibitor combined with penicillin group antibiotics to overcome certain types of antibiotic resistance. It is used to overcome resistance in bacteria that secrete β-lactamase, which otherwise inactivates most penicillins...
and sulbactam
Sulbactam
Sulbactam is a molecule that is given in combination with beta-lactam antibiotics to inhibit beta-lactamase, an enzyme produced by bacteria that destroys the antibiotics...
, thereby showing clinical resistance to the beta-lactam—lactamase inhibitor combinations of amoxicillin
Amoxicillin
Amoxicillin , formerly amoxycillin , and abbreviated amox, is a moderate-spectrum, bacteriolytic, β-lactam antibiotic used to treat bacterial infections caused by susceptible microorganisms. It is usually the drug of choice within the class because it is better absorbed, following oral...
-clavulanate (Co-amoxiclav
Co-amoxiclav
Amoxicillin/clavulanic acid or co-amoxiclav is a combination antibiotic consisting of amoxicillin trihydrate, a β-lactam antibiotic, and potassium clavulanate, a β-lactamase inhibitor...
), ticarcillin
Ticarcillin
Ticarcillin is a carboxypenicillin. It is almost invariably sold and used in combination with clavulanate as Timentin. Because it is a penicillin, it also falls within the larger class of beta-lactam antibiotics. Its main clinical use is as an injectable antibiotic for the treatment of...
-clavulanate, and ampicillin/sulbactam
Ampicillin/sulbactam
Ampicillin/sulbactam is a combination of the common penicillin-derived antibiotic ampicillin and sulbactam, an inhibitor of bacterial beta-lactamase. Two different forms of the drug exist. The first, developed in 1987 and marketed in the United States under the tradename Unasyn, is an intravenous...
, they normally remain susceptible to inhibition by tazobactam
Tazobactam
Tazobactam is a compound that inhibits the action of bacterial beta-lactamases. It is added to the extended spectrum beta-lactam antibiotic piperacillin to produce Tazocin or Zosyn or Piprataz...
and subsequently the combination of piperacillin/tazobactam
Piperacillin/tazobactam
Piperacillin/tazobactam is a combination antibiotic containing the extended-spectrum penicillin antibiotic piperacillin and the β-lactamase inhibitor tazobactam. It is marketed as Kilbac by Morepen and Tazocin or, in the USA, as Zosyn by Wyeth Pharms Inc .-External links:*...
, although resistance has been described. To date, these beta-lactamases have primarily been detected in France and a few other locations within Europe.
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 CitrobacterCitrobacter
Citrobacter is a genus of Gram-negative coliform bacteria in the Enterobacteriaceae family.The species C. amalonaticus, C. koseri, and C. freundii use solely citrate as a carbon source...
, Serratia
Serratia
Serratia is a genus of Gram-negative, facultatively anaerobic, rod-shaped bacteria of the Enterobacteriaceae family. The most common species in the genus, S. marcescens, is normally the only pathogen and usually causes nosocomial infections. However, rare strains of S. plymuthica, S. liquefaciens,...
and Enterobacter
Enterobacter
Enterobacter is a genus of common Gram-negative, facultatively-anaerobic, rod-shaped bacteria of the family Enterobacteriaceae. Several strains of the these bacteria are pathogenic and cause opportunistic infections in immunocompromised hosts and in those who are on mechanical ventilation...
species where its expression is usually inducible; it may also occur on Escherichia coli
Escherichia coli
Escherichia coli is a Gram-negative, rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms . Most E. coli strains are harmless, but some serotypes can cause serious food poisoning in humans, and are occasionally responsible for product recalls...
but is not usually inducible, although it can be hyperexpressed. AmpC type β-lactamases may also be carried on plasmids. AmpC β-lactamases, in contrast to ESBLs, hydrolyse broad and extended-spectrum cephalosporins (cephamycins as well as to oxyimino-β-lactams) but are not inhibited by β-lactamase inhibitors such as clavulanic acid
Clavulanic acid
Clavulanic acid is a competitive β-lactamase inhibitor combined with penicillin group antibiotics to overcome certain types of antibiotic resistance. It is used to overcome resistance in bacteria that secrete β-lactamase, which otherwise inactivates most penicillins...
.
Carbapenemases
Carbapenems are famously stable to AmpC β-lactamases and extended-spectrum-β-lactamases. Carbapenemases are a diverse group of b-lactamases that are active not only against the oxyimino-cephalosporins and cephamycins but also against the carbapenems. Aztreonam is stable to the metallo-β-lactamases,but many IMP and VIM producers are resistant, owing to other mechanisms. Carbapenemases were formerly believed to derive only from classes A, B, and D, but a class C carbapenemase has been described.
IMP-type carbapenemases (one of the metallo-β-lactamases)
Plasmid-mediated IMP-type carbapenemases, 17 varieties of which are currently known, became established in Japan in the 1990s both in enteric Gram-negative organisms and in PseudomonasPseudomonas
Pseudomonas is a genus of gammaproteobacteria, belonging to the family Pseudomonadaceae containing 191 validly described species.Recently, 16S rRNA sequence analysis has redefined the taxonomy of many bacterial species. As a result, the genus Pseudomonas includes strains formerly classified in the...
and Acinetobacter
Acinetobacter
Acinetobacter [asz−in−ée−toe–back−ter] is a genus of Gram-negative bacteria belonging to the Gammaproteobacteria. Acinetobacter species are non-motile and oxidase-negative, and occur in pairs under magnification....
species. IMP enzymes spread slowly to other countries in the Far East, were reported from Europe in 1997, and have been found in Canada and Brazil.
VIM (Verona integron-encoded metallo-β-lactamase)
A second growing family of carbapenemases, the VIM family, was reported from Italy in 1999 and now includes 10 members, which have a wide geographic distribution in Europe, South America, and the Far East and have been found in the United States. VIM-1 was discovered in P. aeruginosa in Italy in 1996; since then, VIM-2 - now the predominant variant - was found repeatedly in Europe and the Far East; VIM-3 and -4 are minor variants of VIM-2 and -1, respectively. VIM enzymes occur mostly in P. aeruginosa, also P. putidaand, very rarely, Enterobacteriaceae.Amino acid sequence diversity is up to 10% in the VIM family, 15% in the IMP family, and 70% between VIM and IMP. Enzymes of both the families, nevertheless, are similar. Both are integron-associated, sometimes within plasmids. Both hydrolyse all β-lactams except monobactams, and evade all β-lactam inhibitors.
OXA (oxacillinase) group of β-lactamases (Class D)
The OXA group of β-lactamases occur mainly in Acinetobacter species and are divided into two clusters. OXA carbapenemases hydrolyse carbapenems very slowly in vitro, and the high MICs seen for some Acinetobacter hosts (>64 mg/L) may reflect secondary mechanisms. They are sometimes augmented in clinical isolates by additional resistance mechanisms, such as impermeability or efflux. OXA carbapenemases also tend to have a reduced hydrolytic efficiency towards penicillins and cephalosporins.KPC (K. pneumoniae carbapenemase) (Class A)
A few class A enzymes, most noted the plasmid-mediated KPC enzymes, are effective carbapenemases as well. Ten variants, KPC-2 through KPC-11 are known, and they are distinguished by one or two amino-acid substitutions (KPC-1 was re-sequenced in 2008 and found to be 100% homologous to published sequences of KPC-2). KPC-1 was found in North Carolina, KPC-2 in Baltimore and KPC-3 in New York. They have only 45% homology with SME and NMC/IMI enzymes and, unlike them, can be encoded by self-transmissible plasmids.The class A Klebsiella pneumoniae
Klebsiella pneumoniae
Klebsiella pneumoniae is a Gram-negative, non-motile, encapsulated, lactose fermenting, facultative anaerobic, rod shaped bacterium found in the normal flora of the mouth, skin, and intestines....
carbapenemase (KPC) is currently the most common carbapenemase, which was first detected in North Carolina
North Carolina
North Carolina is a state located in the southeastern United States. The state borders South Carolina and Georgia to the south, Tennessee to the west and Virginia to the north. North Carolina contains 100 counties. Its capital is Raleigh, and its largest city is Charlotte...
, US, in 1996 and has since spread worldwide. A later publication indicated that Enterobacteriaceae that produce KPC were becoming common in the United States.
CMY (Class C)
The first class C carbapenemase was described in 2006 and was isolated from a virulent strain of Enterobacter aerogenes. It is carried on a plasmid, pYMG-1, and is therefore transmissible to other bacterial strains.SME, IMI, NMC and CcrA
In general, these are of little clinical significance.CcrA (CfiA). Its gene occurs in c. 1-3% of B. fragilis isolates, but fewer produce the enzyme since expression demands appropriate migration of an insertion sequence. CcrA was known before imipenem was introduced, and producers have shown little subsequent increase.
NDM-1 (New Delhi metallo-β-lactamase)
Originally described from New DelhiNew Delhi
New Delhi is the capital city of India. It serves as the centre of the Government of India and the Government of the National Capital Territory of Delhi. New Delhi is situated within the metropolis of Delhi. It is one of the nine districts of Delhi Union Territory. The total area of the city is...
in 2009, this gene is now widespread in Escherichia coli
Escherichia coli
Escherichia coli is a Gram-negative, rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms . Most E. coli strains are harmless, but some serotypes can cause serious food poisoning in humans, and are occasionally responsible for product recalls...
and Klebsiella pneumoniae
Klebsiella pneumoniae
Klebsiella pneumoniae is a Gram-negative, non-motile, encapsulated, lactose fermenting, facultative anaerobic, rod shaped bacterium found in the normal flora of the mouth, skin, and intestines....
from India
India
India , officially the Republic of India , is a country in South Asia. It is the seventh-largest country by geographical area, the second-most populous country with over 1.2 billion people, and the most populous democracy in the world...
and Pakistan
Pakistan
Pakistan , officially the Islamic Republic of Pakistan is a sovereign state in South Asia. It has a coastline along the Arabian Sea and the Gulf of Oman in the south and is bordered by Afghanistan and Iran in the west, India in the east and China in the far northeast. In the north, Tajikistan...
. As of mid-2010, NDM-1 carrying bacteria have been introduced to other countries (including the US and UK), most probably due to the large number of tourists travelling the globe, who may have picked up the strain from the environment, as strains containing the NDM-1 gene have been found in environmental samples in India, by Walsh, et al. 2011.
General Overview
In general, an isolate is suspected to be an ESBL producer when it shows in vitro susceptibility to the second-generation cephalosporinCephalosporin
The cephalosporins are a class of β-lactam antibiotics originally derived from Acremonium, which was previously known as "Cephalosporium".Together with cephamycins they constitute a subgroup of β-lactam antibiotics called cephems.-Medical use:...
s (cefoxitin
Cefoxitin
Cefoxitin is a cephamycin antibiotic developed by Merck & Co., Inc., often grouped with the second−generation cephalosporins. It is sold under the brand name Mefoxin.- Microbiology :...
, cefotetan
Cefotetan
Cefotetan is an injectable antibiotic of the cephamycin type for prophylaxis and treatment of bacterial infections. It is often grouped together with second-generation cephalosporins and has a similar antibacterial spectrum, but with additional anti-anaerobe coverage.Cefotetan was developed by...
) but resistance to the third-generation cephalosporins and to aztreonam
Aztreonam
Aztreonam is a synthetic monocyclic beta-lactam antibiotic , with the nucleus based on a simpler monobactam isolated from Chromobacterium violaceum. It was approved by the U.S. Food and Drug Administration in 1986...
. Moreover, one should suspect these strains when treatment with these agents for Gram-negative infections fails despite reported in vitro susceptibility. Once an ESBL-producing strain is detected, the laboratory should report it as "resistant" to all penicillins, cephalosporins, and aztreonam, even if it is tested (in vitro) as susceptible. Associated resistance to aminoglycosides and trimethoprim
Trimethoprim
Trimethoprim is a bacteriostatic antibiotic mainly used in the prophylaxis and treatment of urinary tract infections.It belongs to the class of chemotherapeutic agents known as dihydrofolate reductase inhibitors...
-sulfamethoxazole
Sulfamethoxazole
Sulfamethoxazole is a sulfonamide bacteriostatic antibiotic.It is most often used as part of a synergistic combination with trimethoprim in a 5:1 ratio in co-trimoxazole , also known under trade names such as Bactrim, Septrin, or Septra; in Eastern Europe it is marketed as Biseptol...
, as well as high frequency of co-existence of fluoroquinolone resistance, creates problems. Beta-lactamase inhibitors such as clavulanate, sulbactam
Sulbactam
Sulbactam is a molecule that is given in combination with beta-lactam antibiotics to inhibit beta-lactamase, an enzyme produced by bacteria that destroys the antibiotics...
, and tazobactam
Tazobactam
Tazobactam is a compound that inhibits the action of bacterial beta-lactamases. It is added to the extended spectrum beta-lactam antibiotic piperacillin to produce Tazocin or Zosyn or Piprataz...
in vitro inhibit most ESBLs, but the clinical effectiveness of beta-lactam/beta-lactamase inhibitor combinations cannot be relied on consistently for therapy. Cephamycins (cefoxitin
Cefoxitin
Cefoxitin is a cephamycin antibiotic developed by Merck & Co., Inc., often grouped with the second−generation cephalosporins. It is sold under the brand name Mefoxin.- Microbiology :...
and cefotetan
Cefotetan
Cefotetan is an injectable antibiotic of the cephamycin type for prophylaxis and treatment of bacterial infections. It is often grouped together with second-generation cephalosporins and has a similar antibacterial spectrum, but with additional anti-anaerobe coverage.Cefotetan was developed by...
) are not hydrolyzed by majority of ESBLs, but are hydrolyzed by associated AmpC-type β-lactamase. Also, β-lactam/β-lactamase inhibitor combinations may not be effective against organisms that produce AmpC-type β-lactamase. Sometimes these strains decrease the expression of outer membrane proteins, rendering them resistant to cephamycins. In vivo studies have yielded mixed results against ESBL-producing K. pneumoniae. (Cefepime
Cefepime
Cefepime is a fourth-generation cephalosporin antibiotic developed in 1994. Cefepime has an extended spectrum of activity against Gram-positive and Gram-negative bacteria, with greater activity against both Gram-negative and Gram-positive organisms than third-generation agents...
, a fourth-generation cephalosporin, has demonstrated in vitro stability in the presence of many ESBL/AmpC strains.) Currently, carbapenems are, in general, regarded as the preferred agent for treatment of infections due to ESBL-producing organisms. Carbapenems are resistant to ESBL-mediated hydrolysis and exhibit excellent in vitro activity against strains of Enterobacteriaceae
Enterobacteriaceae
The Enterobacteriaceae is a large family of bacteria that includes many of the more familiar pathogens, such as Salmonella, Escherichia coli, Yersinia pestis, Klebsiella and Shigella. This family is the only representative in the order Enterobacteriales of the class Gammaproteobacteria in the...
expressing ESBLs.
ESBLs
Strains producing only ESBLs are susceptible to cephamycins and carbapenems in vitro and show little if any inoculum effect with these agents.For organisms producing TEM and SHV type ESBLs, apparent in vitro sensitivity to cefepime
Cefepime
Cefepime is a fourth-generation cephalosporin antibiotic developed in 1994. Cefepime has an extended spectrum of activity against Gram-positive and Gram-negative bacteria, with greater activity against both Gram-negative and Gram-positive organisms than third-generation agents...
and to piperacillin/tazobactam
Piperacillin/tazobactam
Piperacillin/tazobactam is a combination antibiotic containing the extended-spectrum penicillin antibiotic piperacillin and the β-lactamase inhibitor tazobactam. It is marketed as Kilbac by Morepen and Tazocin or, in the USA, as Zosyn by Wyeth Pharms Inc .-External links:*...
is common, but both drugs show an inoculum effect, with diminished susceptibility as the size of the inoculum is increased from 105to 107organisms.
Strains with some CTX-M–type and OXA-type ESBLs are resistant to cefepime
Cefepime
Cefepime is a fourth-generation cephalosporin antibiotic developed in 1994. Cefepime has an extended spectrum of activity against Gram-positive and Gram-negative bacteria, with greater activity against both Gram-negative and Gram-positive organisms than third-generation agents...
on testing, despite the use of a standard inoculum.
Inhibitor-Resistant β-Lactamases
Although the inhibitor-resistant TEM variants are resistant to inhibition by clavulanic acidClavulanic acid
Clavulanic acid is a competitive β-lactamase inhibitor combined with penicillin group antibiotics to overcome certain types of antibiotic resistance. It is used to overcome resistance in bacteria that secrete β-lactamase, which otherwise inactivates most penicillins...
and sulbactam
Sulbactam
Sulbactam is a molecule that is given in combination with beta-lactam antibiotics to inhibit beta-lactamase, an enzyme produced by bacteria that destroys the antibiotics...
, thereby showing clinical resistance to the beta-lactam—lactamase inhibitor combinations of amoxicillin
Amoxicillin
Amoxicillin , formerly amoxycillin , and abbreviated amox, is a moderate-spectrum, bacteriolytic, β-lactam antibiotic used to treat bacterial infections caused by susceptible microorganisms. It is usually the drug of choice within the class because it is better absorbed, following oral...
-clavulanate (Co-amoxiclav
Co-amoxiclav
Amoxicillin/clavulanic acid or co-amoxiclav is a combination antibiotic consisting of amoxicillin trihydrate, a β-lactam antibiotic, and potassium clavulanate, a β-lactamase inhibitor...
), ticarcillin
Ticarcillin
Ticarcillin is a carboxypenicillin. It is almost invariably sold and used in combination with clavulanate as Timentin. Because it is a penicillin, it also falls within the larger class of beta-lactam antibiotics. Its main clinical use is as an injectable antibiotic for the treatment of...
-clavulanate, and ampicillin/sulbactam
Ampicillin/sulbactam
Ampicillin/sulbactam is a combination of the common penicillin-derived antibiotic ampicillin and sulbactam, an inhibitor of bacterial beta-lactamase. Two different forms of the drug exist. The first, developed in 1987 and marketed in the United States under the tradename Unasyn, is an intravenous...
, they remain susceptible to inhibition by tazobactam
Tazobactam
Tazobactam is a compound that inhibits the action of bacterial beta-lactamases. It is added to the extended spectrum beta-lactam antibiotic piperacillin to produce Tazocin or Zosyn or Piprataz...
and subsequently the combination of piperacillin/tazobactam
Piperacillin/tazobactam
Piperacillin/tazobactam is a combination antibiotic containing the extended-spectrum penicillin antibiotic piperacillin and the β-lactamase inhibitor tazobactam. It is marketed as Kilbac by Morepen and Tazocin or, in the USA, as Zosyn by Wyeth Pharms Inc .-External links:*...
.
AmpC
AmpC-producing strains are typically resistant to oxyimino-beta lactams and to cephamycins and are susceptible to carbapenems; however, diminished porin expression can make such a strain carbapenem-resistant as well.Carbapenemases
Strains with IMP-, VIM-, and OXA-type carbapenemases usually remain susceptible to aztreonamAztreonam
Aztreonam is a synthetic monocyclic beta-lactam antibiotic , with the nucleus based on a simpler monobactam isolated from Chromobacterium violaceum. It was approved by the U.S. Food and Drug Administration in 1986...
. Resistance to non–b-lactam antibiotics is common in strains making any of these enzymes, such that alternative options for non–b-lactam therapy need to be determined by direct susceptibility testing. Resistance to fluoroquinolones and aminoglycosides is especially high.
Escherichia coli or Klebsiella
For infections caused by ESBL-producing Escherichia coliEscherichia coli
Escherichia coli is a Gram-negative, rod-shaped bacterium that is commonly found in the lower intestine of warm-blooded organisms . Most E. coli strains are harmless, but some serotypes can cause serious food poisoning in humans, and are occasionally responsible for product recalls...
or Klebsiella
Klebsiella
Klebsiella is a genus of non-motile, Gram-negative, oxidase-negative, rod-shaped bacteria with a prominent polysaccharide-based capsule. It is named after the German microbiologist Edwin Klebs...
species, treatment with imipenem
Imipenem
Imipenem is an intravenous β-lactam antibiotic developed in 1980. It has an extremely broad spectrum of activity.Imipenem belongs to the subgroup of carbapenems. It is derived from a compound called thienamycin, which is produced by the bacterium Streptomyces cattleya...
or meropenem
Meropenem
Meropenem is an ultra-broad spectrum injectable antibiotic used to treat a wide variety of infections, including meningitis and pneumonia. It is a beta-lactam and belongs to the subgroup of carbapenem, similar to imipenem and ertapenem. Meropenem was originally developed by Sumitomo Pharmaceuticals...
has been associated with the best outcomes in terms of survival and bacteriologic clearance. Cefepime
Cefepime
Cefepime is a fourth-generation cephalosporin antibiotic developed in 1994. Cefepime has an extended spectrum of activity against Gram-positive and Gram-negative bacteria, with greater activity against both Gram-negative and Gram-positive organisms than third-generation agents...
and piperacillin/tazobactam
Piperacillin/tazobactam
Piperacillin/tazobactam is a combination antibiotic containing the extended-spectrum penicillin antibiotic piperacillin and the β-lactamase inhibitor tazobactam. It is marketed as Kilbac by Morepen and Tazocin or, in the USA, as Zosyn by Wyeth Pharms Inc .-External links:*...
have been less successful. Ceftriaxone
Ceftriaxone
Ceftriaxone is a third-generation cephalosporin antibiotic. Like other third-generation cephalosporins, it has broad spectrum activity against Gram-positive and Gram-negative bacteria. In most cases, it is considered to be equivalent to cefotaxime in terms of safety and efficacy...
, cefotaxime
Cefotaxime
Cefotaxime is a third-generation cephalosporin antibiotic. Like other third-generation cephalosporins, it has broad spectrum activity against Gram positive and Gram negative bacteria...
, and ceftazidime
Ceftazidime
Ceftazidime is a third-generation cephalosporin antibiotic. Like other third-generation cephalosporins, it has broad spectrum activity against Gram-positive and Gram-negative bacteria. Unlike most third-generation agents, it is active against Pseudomonas aeruginosa, however it has weaker activity...
have failed even more often, despite the organism's susceptibility to the antibiotic in vitro. Several reports have documented failure of cephamycin
Cephamycin
Cephamycins are a group of beta-lactam antibiotics. They are very similar to cephalosporins, and the cephamycins are sometimes classified as cephalosporins.Like cephalosporins, cephamycins are based upon the cephem nucleus...
therapy as a result of resistance due to porin loss. Some patients have responded to aminoglycoside
Aminoglycoside
An aminoglycoside is a molecule or a portion of a molecule composed of amino-modifiedsugars.Several aminoglycosides function as antibiotics that are effective against certain types of bacteria...
or quinolone
Quinolone
The quinolones are a family of synthetic broad-spectrum antibiotics. The term quinolone refers to potent synthetic chemotherapeutic antibacterials....
therapy, but, in a recent comparison of ciprofloxacin
Ciprofloxacin
Ciprofloxacin is a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class.It is a second-generation fluoroquinolone antibacterial. It kills bacteria by interfering with the enzymes that cause DNA to rewind after being copied, which stops synthesis of DNA and of...
and imipenem
Imipenem
Imipenem is an intravenous β-lactam antibiotic developed in 1980. It has an extremely broad spectrum of activity.Imipenem belongs to the subgroup of carbapenems. It is derived from a compound called thienamycin, which is produced by the bacterium Streptomyces cattleya...
for bacteremia involving an ESBL-producing K. pneumoniae, imipenem
Imipenem
Imipenem is an intravenous β-lactam antibiotic developed in 1980. It has an extremely broad spectrum of activity.Imipenem belongs to the subgroup of carbapenems. It is derived from a compound called thienamycin, which is produced by the bacterium Streptomyces cattleya...
produced the better outcome.
Pseudomonas aeruginosa
There have been few clinical studies to define the optimal therapy for infections caused by ESBL producing Pseudomonas aeruginosaPseudomonas aeruginosa
Pseudomonas aeruginosa is a common bacterium that can cause disease in animals, including humans. It is found in soil, water, skin flora, and most man-made environments throughout the world. It thrives not only in normal atmospheres, but also in hypoxic atmospheres, and has, thus, colonized many...
strains.
See also
- ESBL-producing E. coli
- Beta-lactamase inhibitorBeta-lactamase inhibitorA beta-lactamase inhibitor is a drug given in conjunction with a beta-lactam antibiotic. Although the inhibitor does not usually have significant antibiotic activity on its own, it inhibits activity of beta-lactamase, a protein that confers resistance of beta-lactam antibiotics to...