Examples of Bacteria Affected
ß-Lactam Not Affected
Common plasmid-mediated ß-lactamase
Many Gram-negative Ampicillin, ticarcillin, Cefotetan, cefoxitin,
Chromosomal ß-lactamases produced constitutive
Extended-spectrum ß-lactamases related to AmpC
Carbapenem-hydrolyzing chromosomal ß-lactamase bacteria
Plasmid-mediated extended-spectrum ß-lactamases related to the TEM or SHV family
Klebsiella pneumoniae, Escherichia coli, Enterobacter cloacae
Pseudomonas aeruginosa, Enterobacter cloacae, Serratia marcescens
Stenotrophomonas maltophilia, Bacteroides fragilis
Serratia marcescens Enterobacter cloacae piperacillin, firstgeneration cephalosporins
Above listed agents, aztreonam, cefotaxime, ceftazidime, ceftriaxone, ceftizoxime, cefuroxime
Above listed agents, cefoxitin, cefotetan imipenem, meropenem, third-generation cephalosporins, aztreonam
Cefotetan, cefoxitin, imipenem, meropenem, ß-lactamase inhibitors
Imipenem, meropenem Variable
Imipenem, meropenem Variable are produced by nosocomial bacteria and are chromosomally mediated. The stability of third-generation cephalosporins against class I enzyme-producing bacteria occurs because of the effectiveness of the side chains in inhibiting these enzymes. These enzymes are inducible, and under the influence of third-generation cephalosporins that are strong P-lactamase inducers, hyperproduction of the enzyme occurs through a mutational event, resulting in the loss of the repressor gene that controls production of the enzyme (17,18). The bacteria, following loss of the repressor gene, then produce more and more of the enzyme until hydrolysis of the drug occurs, and resistance develops, usually during therapy. Thus, bacteria, such as Enterobacter cloacae, that are initially susceptible to a drug such as ceftazidime can become resistant during therapy. This type of resistance is known as "stable derepression" and when such isolates cause serious infection, they usually remain susceptible to carbapenem antibiotics such as imipenem-cilastatin or meropenem (19).
TEM enzymes are included in the Richmond and Sykes class II-IV P-lactamases and are usually plasmid mediated. These enzymes hydrolyze all penicillins (penicillin, ampicillin, ticarcillin, piperacillin) and some first-generation cephalosporins. Sulfhydryl variable (SHV) enzymes are also included in the Richmond and Sykes class II-IV category and are also encoded on the plasmid. SHV enzymes hydrolyze penicillin and ampicillin but the side chains of ticarcillin and piperacillin offer some stability. TEM and SHV enzymes are produced by a variety of bacteria (predominately community-acquired organisms).
Most recent has been the recognition of extended-spectrum P-lactamases (ESBLs) (20). ESBLs are mutations of common TEM and SHV enzymes that occur under the selection pressure of broad-spectrum cephalosporins such as ceftazidime, ceftriaxone, or cefotaxime. Most ESBLs are inhibited by the carbapenem core structures (imipenem or meropenem), and are also inhibited by the three P-lactamase inhibitors, sulbactam, clavu-lanic acid, and tazobactam (21). However, as a response to the increased use of peni-cillin-P-lactamase inhibitor combinations, additional mutations of common TEM enzymes have now been reported. These so-called inhibitor-resistant TEMS (IRTs) are not inhibited by any of the three available P-lactamase inhibitors. While such enzymes are rare at present, it is reasonable to expect that as the use of drugs such as ticarcillin-clavu-lanic acid, ampicillin-sulbactam, piperacillin-tazobactam, and amoxacillin-clavulanic acid increases, the incidence of IRTs will continue to increase. In a like manner, as the use of carbapenem antibiotics increases, the number of bacteria that produce so-called car-bapenase enzymes will also increase. Table 6 gives examples of P-lactamase-induced resistance in Gram-negative bacteria.
There are three basic ways to inhibit a P-lactamase. First, alteration/addition of side chains to the basic P-lactam core prevents the enzyme from hydrolyzing the lactam bond (22). As a general rule, the rank order stability of drugs to common P-lactamases based on side chains is: penicillins < first-generation cephalosporins < second-generation cephalosporins < third-generation cephalosporins. A second way to inhibit a P-lac-tamase is to alter the P-lactam core. The penicillin P-lactam ring is the easiest to hydrolyze followed by the cephalosporin ring, followed by the monobactam ring, followed by the carbapenem ring. A third method of P-lactamase inhibition is the addition of a P-lactamase inhibitor to a P-lactamase unstable antibiotic such as a penicillin. There are at present four such antibiotics, ampicillin-sulbactam, amoxacillin-clavu-lanic acid, ticarcillin-clavulanic acid, and piperacillin-tazobactam. Although these P-lactamase inhibitors differ in their potency and clinical dose, they all inhibit Richmond and Sykes class II-VI enzymes but have no inhibitory effect on class I enzymes. Table 7 lists Gram-negative bacteria that produce P-lactamases that are usually inhibited by the P-lactamase inhibitors along with the percentage of isolates that produced P-lacta-mase at the University of Kentucky Hospital during 1998. Only the side chains on third-generation cephalosporins or chemical alteration of the P-lactam core to either a monobactam (aztreonam) or a carbapenem (imipenem or meropenem) can inhibit class I enzymes.
ESBLs result from the selection pressure of third-generation cephalosporins (23). Klebsiella pneumoniae is the most frequently implicated bacteria followed by Escherichia coli. ESBL production has been reported in many other Gram-negative bacteria as well. In one ICU study, K. pneumoniae resistance to ceftazidime increased
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