Emergence of resistance in gram-negative bacteria during therapy with expanded-spectrum cephalosporins

Antimicrobial resistance is an emerging problem among nosocomial bacteria. Risk factors for the recovery of ceftriaxone-resistant (CRCF) or -susceptible (CSCF) Citrobacter freundii in clinical cultures from hospitalized patients were determined by using a case-case-control study design. CRCF was isolated from 43 patients (case group 1) and CSCF was isolated from 87 patients (case group 2) over a 3-year period. Risk factors for CRCF were exposure to imipenem (odds ratio [OR], 7.5; 95% confidence interval [CI], 1.2 to 45.4), broadspectrum cephalosporins (OR, 6.9; 95% CI, 1.8 to 26.7), vancomycin (OR, 3.0; 95% CI, 1.2 to 7.4), or piperacillin-tazobactam (OR, 2.6; 95% CI, 1.1 to 6.2), as well as hospital length of stay >1 week (OR, 3.6; 95% CI, 1.3 to 10.2) and intensive care unit (ICU) stay (OR, 2.6; 95% CI, 1.1 to 6.2). Risk factors for CSCF were peripheral vascular disease (OR, 23.2; 95% CI, 4.3 to 124.6), AIDS (OR, 9.5; 95% CI, 1.6 to 55.5), cerebrovascular disease (OR, 4.2; 95% CI, 1.6 to 10.8), and ICU stay (OR, 3.1; 95% CI, 1.8 to 5.4).

Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Epidemiological Risk Factors for Isolation of Ceftriaxone-Resistant versus -Susceptible Citrobacter freundii in Hospitalized Patients

Kim

Harris

Roghmann

et al. 2003

“…However, resistance to these agents has developed during their clinical use. Resistance to the expanded-spectrum cephalosporins may result in up to one-half of patients infected with Pseudomonas aeruginosa, Entierobacter spp., or Serratia marcescens during or after therapy and is primarily,the result of p-lactamase overproduction (5,16). Resistance to specific aminoglycosides with the exception of amikacin has been observed in medical centers where usage was extensive (2, 7.…”

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confidence: 99%

In vitro activities of cefepime alone and with amikacin against aminoglycoside-resistant gram-negative bacteria

Fung‐Tomc

Huczko

Kolek

et al. 1991

The in vitro activity of cefepime was compared with those of ceftazidime, cefotaxime, and cefpfrome against amlnoglycoside..resistaAit gram-negative bacteria. Cefepime was the most active cephalosporin, with a MIC for 90% of strains tested for all non-Pseudomonas aeruginosa species of c4 txg/mI. No cefepime resistance was encountered among members of the family Enterobacteriaceae. Of the 40 aminoglycoside-resistant P. aeruginosa isolates, 15% were resistant to cefepime, compared with 18% for ceftazidime, 30% for cefpirome, and 35% for celotaxime. Synersm between cefepime and amikacin was observed and occurred most frequently in P. aeruginosa strains resistant to. cefepime but susceptible to amikacin. In no case did cefepime and amikacin exhibit antagonism against P. aeruginosa.Broad-spectrum cephalosporins and aminoglycosides are highly active against aerobic gram-negative bacteria. However, resistance to these agents has developed during their clinical use. Resistance to the expanded-spectrum cephalosporins may result in up to one-half of patients infected with Pseudomonas aeruginosa, Entierobacter spp., or Serratia marcescens during or after therapy and is primarily,the result of p-lactamase overproduction (5, 16). Resistance to specific aminoglycosides with the exception of amikacin has been observed in medical centers where usage was extensive (2, 7. 11).Cefepime is geaerally active against gram-negative bacteria resistant to other br.oad-spectrum cephalosporins. No cefepime resistance was observed among cefotaxime-and/or ceftazidime-resistant members of the family -Enterobacteriaceae (6, 8). Even With a group of cefotaxime-and/or ceftazidime-resistant P. aeruginosa strains, 81% of the strains continued to be susceptible to cefepime (6).In this study, we determined the activities of cefepime and other broad-spectrum cephalosporins against 240 aminoglycoside-resistant gram-negative bacteria. We also determined whether cefepime and amikacin acted synergistically and whether this synergism occurred equally among strains with different susceptibilities to.cefepime and amikacin. Of the 240 aminoglycoside-resistant bacteria, 222 were resistant to gentamicin (MIC, .16 pug/ml), 212 were resistant to tobramycin (MIC, .64 ,ug/ml), and 27 were resistant to amikacin (MIC, -64 ,ug/ml). Overall, cefepime was more active than cefpirome, ceftazidime, and cefotaxime against the aminoglycoside-resistant strains (Table 1). The MICs for 90% of strains tested of cefotaxime for S. marcescens, Enterobacter cloacae, Escherichia coli, and P. aeruginosa were 64 to 128 ,ug/ml, which is in the resistant interpretative range for cefotaxime (14). When MICs of .64 ,ug/ml for cefotaxime and .32 ,ug/ml for cefepime, cefpirome, and ceftazidime were used as the breakpoints for resistance (14), 6 strains were resistant to cefepime, 13 were resistant to cefpirome, 12 were resistant to ceftazidime, and 21 were resistant to cefotaxime. All six cefepime-resistant strains were P. aeruginosa. There was no association between resistance to cefepime ...

“…On the other hand, the inhibitory activity of BRL 42715 extends to all of the class I cephalosporinase enzymes. Many of the organisms which produce a class I ,-lactamase show inducible expression of the enzyme (20), but there are a growing number of reports of isolates which have high-level constitutive expression of the enzyme (4,7,22). Such overproducers are resistant to broad-spectrum cephalosporins, and one interesting property of BRL 42715 is its ability to neutralize this resistance and render many of these organisms fully susceptible.…”

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confidence: 99%

In vitro evaluation of BRL 42715, a novel beta-lactamase inhibitor

Coleman

Griffin

Page

et al. 1989

The penem BRL 42715, C6-(N1-methyl-1,2,3-triazolylmethylene)penem, is a potent inhibitor of a broad range of bacterial P-lactamases, including the plasmid-mediated TEM, SHV, OXA, and staphylococcal enzymes, as well as the chromosomally mediated enzymes of Bacteroides, Enterobacter, Citrobacter, Serratia, Morganella, Escherichia, Klebsiella, and Proteus species. The concentration of BRL 42715 needed to reduce the initial rate of hydrolysis of most P-lactamase enzymes by 50% was <0.01 ,ug/ml, which was 10-to 100-fold lower than for other l-lactamase inhibitors. These potent inhibitory activities were reflected in the low concentrations of BRL 42715 needed to potentiate the antibacterial activity of ,-lactamase-susceptible Il-lactams. Concentrations of 0.25 ,ug/ml or less considerably enhanced the activity of amoxicillin against many jI-lactamase-producing strains. The MIC50 (MIC for 50% of strains tested) of amoxicillin for 412 ,3-lactamase-producing members of the family Enterobacteriaceae fell from >128 to 2 ,ug/ml in the presence of 1 jig of BRL 42715 per ml, whereas 5 jig of clavulanic acid per ml brought the MIC5. down to 8 jig/ml. Among these 412 strains were 73 Citrobacter and Enterobacter strains, and 1 ,ig of BRL 42715 per ml reduced the M1C50 of amoxicillin from >128 to 2 ,ug/mI for the 48 cefotaxime-susceptible strains and from >128 to 8 ,ig/ml for the 25 cefotaxime-resistant strains.The ,B-lactamase enzymes form a large and diverse group (3,19) and are recognized as a major cause of bacterial resistance to P-lactam antibiotics (14). This resistance can often be overcome either by using P-lactam antibiotics that are stable to hydrolysis by P-lactamases or by combining labile 3-lactams with enzyme inhibitors which may not themselves be useful antibacterial agents but which have the ability to inactivate P-lactamases. The first ,-lactamase inhibitor to have clinical application was clavulanic acid (8, 16), and formulations of amoxicillin plus clavulanic acid and of ticarcillin plus clavulanic acid are available which protect the antibiotics amoxicillin and ticarcillin from hydrolysis by many P-lactamase-producing organisms. More recently described P-lactamase inhibitors include sulbactam (5) and tazobactam (YTR 830; 1). Clavulanic acid is highly active against a broad range of P-lactamases, including the Ic enzymes produced by Proteus vulgaris and Bacteroides fragilis, but is only weakly active against other class I enzymes. Sulbactam is generally less potent than clavulanic acid (9), although it does have some activity against most class I enzymes, while tazobactam is similar in potency to clavulanic acid and also has moderate activity against the class I enzymes.Studies done in our laboratories on the structural modification of the penem nucleus culminated in the synthesis of compounds containing an alkylidene moiety at the C6 position of the penem ring system (I.