Emergence of Resistance During Therapy with the Newer  -Lactam Antibiotics: Role of Inducible  -Lactamases and Implications for the Future

Cc, Sanders; We, Sanders

doi:10.1093/clinids/5.4.639

Cited by 275 publications

(122 citation statements)

References 70 publications

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“…In this scenario, patients are treated with an appropriate ␤-lactam based on initial susceptibility data, only to fail therapy due to the emergence of AmpC-mediated resistance. This phenomenon has been observed in 14 to 56% of patients treated with antipseudomonal penicillins, penicillin-inhibitor combinations, aztreonam, and extended-spectrum cephalosporins (50,71,94,97,118,147,226,228,235), and emergence of resistance/ clinical failure is observed most frequently with infections outside the urinary tract and in patients with underlying cystic fibrosis and neutropenia. Although combining an aminoglyco- Inducing ␤-lactams, such as cefoxitin and imipenem, cross the outer membrane through porins, enter the periplasmic space, and interact with target PBPs.…”

Section: Clinical Significance Of Ampc Overproductionmentioning

confidence: 99%

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

2009

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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.

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Section: Clinical Significance Of Ampc Overproductionmentioning

confidence: 99%

“…22,2009 ANTIBACTERIAL-RESISTANT PSEUDOMONAS AERUGINOSA 589 side with an antipseudomonal ␤-lactam is one strategy for preventing the emergence of AmpC-mediated resistance, this combination is not always effective in achieving that goal (97,118,147,226,228,235).…”

Section: Clinical Significance Of Ampc Overproductionmentioning

confidence: 99%

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

2009

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“…P-lactamase have been shown to be responsible for a number of clinical failures associated with emergence of resistance during therapy with the newer expanded-spectrum ,-lactam antibiotics (16). These mutants occur spontaneously at a frequency of 10-6 to 10-7 and appear to have lost control of P-lactamase production (8,10).…”

mentioning

confidence: 99%

“…Loss of this normal control mechanism via mutation leads to high-level Ilactamase production. This event is associated with resistance to multiple P-lactam antibiotics (8,10,14,16). This resistance has been difficult to explain solely on the basis of P-lactamase-mediated hydrolysis because it involves many drugs that appear to be poor substrates for the enzyme.…”

mentioning

confidence: 99%

Role of beta-lactamases and outer membrane proteins in multiple beta-lactam resistance of Enterobacter cloacae

Werner¹,

Sanders²,

Sanders³

et al. 1985

Antimicrob Agents Chemother

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The chromosomal I-lactamase and outer membrane proteins of Enterobacter cloacae were examined to determine their relative contributions to multiple antibiotic resistance in this organism. Mutants altered in I(-lactamase expression, whether derived in the laboratory or recovered from patients treated with one of the new ,-lactam antibiotics, were found to have no detectable alterations in outer membrane proteins. Derepression of ,I-lactamase in these mutants was associated with high-level resistance to multiple I-lactam antibiotics, while loss of inducible ,-lactamase (i.e., production of basal enzyme levels only) was associated with acquisition of susceptibility to many ,-lactam antibiotics, including cephalothin. In contrast, alteration in outer membrane proteins was associated with only moderate-leVel resistance to P-lactam antibiotics. However, this included resistance to such drugs as amdinocillin and Sch 34343, which were unaffected by derepression of P-lactalnase. Resistance to chloramphenicol and tetracycline also accompanied changes in outer membrane proteins. Although the outer membrane proteins of various strains of E. cloacae were similar, there did appear to be some major strain-to-strain variations. Thus, it appears that alterations in both 13-lactamase and outer membrane proteins can affect the susceptibility of E. cloacae to many antibiotics. However, alterations in P-lactamase alone are sufficient to produce high-level multiple 3-lactam resistance in this organism.Mutants of Enterobacter spp. producing high levels of P-lactamase have been shown to be responsible for a number of clinical failures associated with emergence of resistance during therapy with the newer expanded-spectrum ,-lactam antibiotics (16). These mutants occur spontaneously at a frequency of 10-6 to 10-7 and appear to have lost control of P-lactamase production (8, 10). Normally, production of the chromosomally mediated cephalosporinase of Enterobacter spp. is under repressor control (8). Loss of this normal control mechanism via mutation leads to high-level Ilactamase production. This event is associated with resistance to multiple P-lactam antibiotics (8, 10, 14, 16). This resistance has been difficult to explain solely on the basis of P-lactamase-mediated hydrolysis because it involves many drugs that appear to be poor substrates for the enzyme. Thus, it has been speculated that this resistance must also involve a change in permeability.The permeability of gram-negative organisms to ,B-lactam antibiotics is determined primarily by outer membrane proteins (13). Studies by Sawai et al. (17) and Kaneko et al. (9) indicate that in Enterobacter cloacae two major outer membrane proteins appear to be involved in cephalosporin permeation. Alterations in these proteins have been shown to be associated with multiple P-lactam resistance in this organism (17). Since changes in P-lactamase expression and outer membrane proteins can be responsible for multiple 13-lactam resistance, this investigation was designed to examine both these fact...

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“…MICs were not (or only by one dilution) elevated against Citrobacter and Enterobacter strains, highly resistant to third-generation cephalosporins. This behaviour reflects the extreme stability of the drug to /Mactamases, since it has been shown that cephalosporin resistance in such strains is due to chromosomal cephalosporinase (Sanders & Sanders 1983, Seeberg et al, 1983. Sch 34343, thus, together with imipenem, can be considered as potent chemotherapeutic agents in infections caused by Enterobacteriaceae resistant to third-generation cephalosporins and to aztreonam.…”

Section: Discussionmentioning

confidence: 99%

Comparative activity of the penem antibiotic Sch 34343 against Gram-negative and Gram-positive bacteria with special reference to multiresistant strains

Kayser

Novak

Strässle

1985

Journal of Antimicrobial Chemotherapy

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A new penem antibiotic, Sch 34343, was shown to be active against a large number of Gram-positive bacteria. The drug inhibited peniciUinase-positive and -negative staphylococci equally well, being five times more active than cefamandole and ten times more active than methiallin. Most methicillin-resistant staphylococci were inhibited by concentrations between 0-25 and 4 mg/1, but a small group of highly resistant strains were observed. Sch 34343 was eight times less active than ampicillin and penicillin G, but as active as piperacilhn against enterococci. The drug showed excellent activity against various streptococci. Sch 34343 was as bactericidal as flucloxacilhn, ampicillin and penicillin G against staphylococci, enterococci and streptococci, respectively, in lulling kinetic tests Enterobacteriaceae susceptible to third-generation cephalosporins were approximately five times less susceptible to Sch 34343, but MICs were far below the susceptibility breakpoint Sch 34343 was equally active against Citrobacter and Enterobacter strains that were highly resistant to third-generation cephalosporins and to aztreonam. Together with thienamycin, this drug seems to be a good alternative for the treatment of infections caused by bacteria resistant to thirdgeneration cephalosporins and to aztreonam.

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Emergence of Resistance During Therapy with the Newer -Lactam Antibiotics: Role of Inducible -Lactamases and Implications for the Future

Cited by 275 publications

References 70 publications

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

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

Role of beta-lactamases and outer membrane proteins in multiple beta-lactam resistance of Enterobacter cloacae

Comparative activity of the penem antibiotic Sch 34343 against Gram-negative and Gram-positive bacteria with special reference to multiresistant strains

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