C. C. Sanders

Bio: C. C. Sanders is an academic researcher from Creighton University. The author has contributed to research in topics: Enterobacteriaceae. The author has an hindex of 1, co-authored 1 publications receiving 161 citations.

AmpC β-Lactamases

Abstract: Summary: AmpC β-lactamases are clinically important cephalosporinases encoded on the chromosomes of many of the Enterobacteriaceae and a few other organisms, where they mediate resistance to cephalothin, cefazolin, cefoxitin, most penicillins, and β-lactamase inhibitor-β-lactam combinations. In many bacteria, AmpC enzymes are inducible and can be expressed at high levels by mutation. Overexpression confers resistance to broad-spectrum cephalosporins including cefotaxime, ceftazidime, and ceftriaxone and is a problem especially in infections due to Enterobacter aerogenes and Enterobacter cloacae, where an isolate initially susceptible to these agents may become resistant upon therapy. Transmissible plasmids have acquired genes for AmpC enzymes, which consequently can now appear in bacteria lacking or poorly expressing a chromosomal blaAmpC gene, such as Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis. Resistance due to plasmid-mediated AmpC enzymes is less common than extended-spectrum β-lactamase production in most parts of the world but may be both harder to detect and broader in spectrum. AmpC enzymes encoded by both chromosomal and plasmid genes are also evolving to hydrolyze broad-spectrum cephalosporins more efficiently. Techniques to identify AmpC β-lactamase-producing isolates are available but are still evolving and are not yet optimized for the clinical laboratory, which probably now underestimates this resistance mechanism. Carbapenems can usually be used to treat infections due to AmpC-producing bacteria, but carbapenem resistance can arise in some organisms by mutations that reduce influx (outer membrane porin loss) or enhance efflux (efflux pump activation).

Antibacterial-Resistant Pseudomonas aeruginosa: Clinical Impact and Complex Regulation of Chromosomally Encoded Resistance Mechanisms

Abstract: Summary: Treatment of infectious diseases becomes more challenging with each passing year. This is especially true for infections caused by the opportunistic pathogen Pseudomonas aeruginosa, with its ability to rapidly develop resistance to multiple classes of antibiotics. Although the import of resistance mechanisms on mobile genetic elements is always a concern, the most difficult challenge we face with P. aeruginosa is its ability to rapidly develop resistance during the course of treating an infection. The chromosomally encoded AmpC cephalosporinase, the outer membrane porin OprD, and the multidrug efflux pumps are particularly relevant to this therapeutic challenge. The discussion presented in this review highlights the clinical significance of these chromosomally encoded resistance mechanisms, as well as the complex mechanisms/pathways by which P. aeruginosa regulates their expression. Although a great deal of knowledge has been gained toward understanding the regulation of AmpC, OprD, and efflux pumps in P. aeruginosa, it is clear that we have much to learn about how this resourceful pathogen coregulates different resistance mechanisms to overcome the antibacterial challenges it faces.

Growing group of extended-spectrum beta-lactamases: the CTX-M enzymes.

Abstract: The production of β-lactamases is the predominant cause of resistance to β-lactam antibiotics in gram-negative bacteria. These enzymes cleave the amide bond in the β-lactam ring, rendering β-lactam antibiotics harmless to bacteria. They are classified according to the scheme of Ambler et al. (2) into four classes, designated classes A to D, on the basis of their amino acid sequences, with classes A and C being the most frequently occurring among bacteria. Oxyimino-cephalosporins such as cefotaxime and ceftazidime, which are inherently less susceptible to β-lactamases, were introduced in the early 1980s to treat infections caused by gram-negative bacilli that were resistant to established β-lactams and that produced class A, C, and D β-lactamases. Their repetitive and increased use induced the appearance of resistant strains, which overproduced class C enzymes (42, 72) and/or which produced extended-spectrum β-lactamases (ESBLs), mainly those of class A but also those of class D (19, 61). Class A ESBLs hydrolyze oxyimino-cephalosporins and aztreonam but not 7-α-substituted β-lactams. They are generally susceptible to β-lactamase inhibitors (clavulanate, sulbactam, tazobactam). According to the functional classification scheme of Bush et al. (23), class A ESBLs are therefore clustered in group 2be, which can be subdivided on the basis of their activities against ceftazidime and cefotaxime as ceftazidimases (higher levels of hydrolytic activity against ceftazidime than against cefotaxime) and cefotaximases (higher levels of hydrolytic activity against cefotaxime than against ceftazidime), respectively (48). However, class A ESBLs form a heterogeneous molecular cluster comprising β-lactamases sharing 20 to >99% identity. The earliest class A ESBLs, which were reported from 1985 to 1987, differed from widespread plasmid-mediated TEM-1/2 and SHV-1 penicillinases by one to four point mutations, which extend their hydrolytic spectra (51, 90, 91). TEM and SVH ESBLs now comprise at least 130 members and have a worldwide distribution. Most of them are ceftazidimases, and only a few are cefotaximases. More recently, non-TEM and non-SHV plasmid-mediated class A ESBLs have been reported: ceftazidimases of the PER, VEB, TLA-1, and GES/IBC types and cefotaximases of the SFO-1, BES-1, and CTX-M types (8, 12, 13, 16, 31, 58, 62, 75, 76, 79, 81, 88, 96). The CTX-M β-lactamases are the most widespread enzymes. They were initially reported in the second half of the 1980s, and their rate of dissemination among bacteria and in most parts of the world has increased dramatically since 1995. This review focuses on the origin, epidemiology, clinical impact, enzymatic properties, and structural relationships of the CTX-M-type ESBLs.

Detection of plasmid-mediated ampc beta-lactamase genes in clinical isolates by using multiplex pcr

Abstract: Therapeutic options for infections caused by gram-negative organisms expressing plasmid-mediated AmpC β-lactamases are limited because these organisms are usually resistant to all the β-lactam antibiotics, except for cefepime, cefpirome, and the carbapenems. These organisms are a major concern in nosocomial infections and should therefore be monitored in surveillance studies. Six families of plasmid-mediated AmpC β-lactamases have been identified, but no phenotypic test can differentiate among them, a fact which creates problems for surveillance and epidemiology studies. This report describes the development of a multiplex PCR for the purpose of identifying family-specific AmpC β-lactamase genes within gram-negative pathogens. The PCR uses six sets of ampC-specific primers resulting in amplicons that range from 190 bp to 520 bp and that are easily distinguished by gel electrophoresis. ampC multiplex PCR differentiated the six plasmid-mediated ampC-specific families in organisms such as Klebsiella pneumoniae, Escherichia coli, Proteus mirabilis, and Salmonella enterica serovar Typhimurium. Family-specific primers did not amplify genes from the other families of ampC genes. Furthermore, this PCR-based assay differentiated multiple genes within one reaction. In addition, WAVE technology, a high-pressure liquid chromatography-based separation system, was used as a way of decreasing analysis time and increasing the sensitivity of multiple-gene assays. In conclusion, a multiplex PCR technique was developed for identifying family-specific ampC genes responsible for AmpC β-lactamase expression in organisms with or without a chromosomal AmpC β-lactamase gene.

Three Decades of β-Lactamase Inhibitors

Abstract: Summary: Since the introduction of penicillin, β-lactam antibiotics have been the antimicrobial agents of choice. Unfortunately, the efficacy of these life-saving antibiotics is significantly threatened by bacterial β-lactamases. β-Lactamases are now responsible for resistance to penicillins, extended-spectrum cephalosporins, monobactams, and carbapenems. In order to overcome β-lactamase-mediated resistance, β-lactamase inhibitors (clavulanate, sulbactam, and tazobactam) were introduced into clinical practice. These inhibitors greatly enhance the efficacy of their partner β-lactams (amoxicillin, ampicillin, piperacillin, and ticarcillin) in the treatment of serious Enterobacteriaceae and penicillin-resistant staphylococcal infections. However, selective pressure from excess antibiotic use accelerated the emergence of resistance to β-lactam-β-lactamase inhibitor combinations. Furthermore, the prevalence of clinically relevant β-lactamases from other classes that are resistant to inhibition is rapidly increasing. There is an urgent need for effective inhibitors that can restore the activity of β-lactams. Here, we review the catalytic mechanisms of each β-lactamase class. We then discuss approaches for circumventing β-lactamase-mediated resistance, including properties and characteristics of mechanism-based inactivators. We next highlight the mechanisms of action and salient clinical and microbiological features of β-lactamase inhibitors. We also emphasize their therapeutic applications. We close by focusing on novel compounds and the chemical features of these agents that may contribute to a “second generation” of inhibitors. The goal for the next 3 decades will be to design inhibitors that will be effective for more than a single class of β-lactamases.