Antibiotic Options for Treatment of Pediatric Infections with Enterobacteriaceae Producing Broad Spectrum Beta-Lactamases

2012 ◽  
Vol 10 (2) ◽  
pp. 130-135
Author(s):  
Xuan Qin ◽  
Emmanouil Galanakis ◽  
Danielle M. Zerr ◽  
Scott J. Weissman
Keyword(s):  
Broad Spectrum ◽  
Beta Lactamases ◽  
Pediatric Infections

scholarly journals Properties of IRT-14 (TEM-45), a newly characterized mutant of TEM-type beta-lactamases.

1997 ◽  
Vol 41 (2) ◽  
pp. 374-378 ◽  
Author(s):  
M M Caniça ◽  
M Barthélémy ◽  
L Gilly ◽  
R Labia ◽  
R Krishnamoorthy ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Kinetic Parameters ◽  
Clavulanic Acid ◽  
Broad Spectrum ◽  
Promoter Region ◽  
Beta Lactamase ◽  
Beta Lactamases ◽  
Structural Modifications ◽  
E Coli

IRT-14 (TEM-45) is a new mutant TEM-type beta-lactamase that was isolated from clinical Escherichia coli P37 and that confers resistance to broad-spectrum penicillins with reduced sensitivity to beta-lactamase inhibitors. The MICs of amoxicillin alone and of amoxicillin combined with 2 micrograms of clavulanic acid or 2 micrograms of tazobactam per ml were 4,096, 2,048, and 1,024 micrograms/ml, respectively. The strain was susceptible to cephalosporins, aztreonam, moxalactam, and imipenem. The enzyme was purified to homogeneity, and values of the kinetic parameters Kcat, Km, and Kcat/Km were determined for different substrates. This enzyme, with a pI of 5.2, was found to have reduced affinity for broad-spectrum penicillins and cephalosporins. The values of 50% inhibitory concentrations of clavulanic acid, sulbactam, tazobactam, and brobactam are correlated with the higher KmS for substrates. The resistance of E. coli P37 to mechanism-based inactivators results from a higher level of production of the TEM-derived enzyme due to the G-to-T substitution at position 162 (G-162-->T) in the promoter region of blaTEM and from the structural modifications resulting from the Met-69-->Leu and Arg-275-->Gln substitutions that characterize IRT-14 beta-lactamase.

scholarly journals Phenotypic detection of broad-spectrum beta-lactamases in microbiological practice

2011 ◽  
Vol 17 (5) ◽  
pp. BR147-BR152 ◽  
Author(s):  
Miroslava Htoutou Sedlakova ◽  
Vojtech Hanulik ◽  
Magdalena Chroma ◽  
Kristyna Hricova ◽  
Milan Kolar ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Beta Lactamases

scholarly journals Incidence of fecal Enterobacteriaceae producing broad-spectrum beta-lactamases in patients with hematological malignancies

2015 ◽  
Vol 159 (1) ◽  
pp. 100-103 ◽  
Author(s):  
Milan Kolar ◽  
Miroslava Htoutou Sedlakova ◽  
Vendula Pudova ◽  
Magdalena Roderova ◽  
Jiri Novosad ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Hematological Malignancies ◽  
Beta Lactamases

The Ultra-Broad-Spectrum Beta-lactamase Inhibitor QPX7728 Restores the Potency of Multiple Oral Beta-lactam Antibiotics against Beta-lactamase Producing Strains of Resistant Enterobacterales

2021 ◽  
Author(s):  
Olga Lomovskaya ◽  
Debora Rubio-Aparicio ◽  
Ruslan Tsivkovski ◽  
Jeff Loutit ◽  
Michael Dudley
Keyword(s):  
Broad Spectrum ◽  
Resistance Mechanisms ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Intrinsic Resistance ◽  
Beta Lactamases ◽  
Beta Lactam Antibiotics ◽  
The Impact ◽  
Lactamase Inhibitor

QPX7728 is a cyclic boronate ultra-broad-spectrum beta-lactamase inhibitor, with potent activity against both serine and metallo beta-lactamases. QPX7728 can be delivered systemically by the IV or oral route of administration. Oral β-lactam antibiotics alone or in combination with QPX7728 were evaluated for 1) sensitivity to hydrolysis by various common beta-lactamases and inhibition of hydrolysis by QPX7728; 2) the impact of non-beta-lactamase-mediated resistance mechanisms on potency of beta-lactams; and 3) in vitro activity against a panel of clinical strains producing diverse beta-lactamases. The carbapenem tebipenem had stability for many serine beta-lactamases from all molecular classes followed by cephalosporin ceftibuten. Addition of QPX7728 to tebipenem, ceftibuten and mecillinam completely reversed beta-lactamase-mediated resistance in cloned beta-lactamases from serine and metallo enzyme classes; the degree of potentiation of other beta-lactams varied according to the beta-lactamase produced. Tebipenem, ceftibuten and cefixime had the lowest MICs against laboratory strains with various combinations of beta-lactamases and the intrinsic drug-resistance mechanisms of porin and efflux mutations. There was a high degree of correlation between potency of various combinations against cloned beta-lactamases and efflux/porin mutants and the activity against clinical isolates, showing the importance of both inhibition of beta-lactamase along with minimal impact of general intrinsic resistance mechanisms affecting the beta-lactam. Tebipenem and ceftibuten appeared to be the best beta-lactam antibiotics when combined with QPX7728 for activity against Enterobacterales that produce serine or metallo beta-lactamases.

scholarly journals Analyses of Plasmids Harbouring Quinolone Resistance Determinants in Enterobacteriaceae Members

2017 ◽  
Vol 66 (4) ◽  
pp. 529-532
Author(s):  
Bayri Erac ◽  
Fethiye Ferda Yilmaz ◽  
Ismail Ozturk ◽  
Sabire Sohret Aydemir ◽  
Mine Hosgor-Limoncu
Keyword(s):  
Broad Spectrum ◽  
Quinolone Resistance ◽  
Clinical Isolates ◽  
Conjugative Plasmid ◽  
Beta Lactamase ◽  
Beta Lactamases ◽  
Conjugative Plasmids ◽  
Resistance Determinants ◽  
Resistance Plasmids ◽  
Lactamase Gene

The aim of this study was to explore the plasmid characteristics of eight clinical Enterobacteriaceae strains containing extended broad spectrum beta-lactamases and plasmid-mediated quinolone resistance. Plasmids were transferred by conjugation or transformation and resistance determinants were investigated by PCR. We showed that at least one plasmid harbouring qnrB or qnrS determinant was transferred by conjugation in five isolates. QepA determinant was confirmed to be on a non-conjugative plasmid. We found at least one beta-lactamase gene in seven of the eight clinical isolates having plasmid-mediated quinolone resistance, which indicated that these two resistance determinants were mostly on the same conjugative plasmids.

scholarly journals Pharmacodynamics of Ceftolozane Combined with Tazobactam againstEnterobacteriaceaein a Neutropenic Mouse Thigh Model.

2016 ◽  
pp. AAC.01580-16 ◽  
Author(s):  
M. J. Melchers ◽  
E Mavridou ◽  
A. C van Mil ◽  
C. Lagarde ◽  
J.W. Mouton
Keyword(s):  
Broad Spectrum ◽  
Beta Lactamases ◽  
Emax Model ◽  
Daily Dose ◽  
Before And After ◽  
Extended Spectrum Beta Lactamases ◽  
Static Effect ◽  
The Mean ◽  
Concentration Threshold ◽  
Best Fit

Ceftolozane is a new broad-spectrum cephalosporin and combined with tazobactam to broaden its activity against strains producing extended spectrum beta-lactamases (ESBL). We determined the pharmacodynamics (PD) of the combination in the neutropenic mouse thigh model to determine the optimal exposure of tazobactam. Treatment was started in CD-1 neutropenic mice 2h after infection with ceftolozane q2h alone or in combination with tazobactam using different dose frequencies for 24h and cfu determined in the thighs before and after treatment. The Emax model was fit to the dose and PK/PD index (PDI) responses to determine the PDI values of ceftolozane alone and in combination with tazobactam resulting in a static effect and 1 log kill. The effect of tazobactam was dependent on the time above a concentration threshold %fT>CTwhereby the q2h was more efficacious than q8h, reducing the tazobactam daily dose by a factor 6.9 to 59.0 (n=3 strains) to obtain a static effect. Using R2as an indicator of the best fit of %fT>CT —response relationships, the CTbest correlating varied between 0.5 and 2 mg/L, depending on the strain. A similar result was obtained when analysing the q2h vs q8h regimens. For all isolates tested, the mean %fT>CT0.5 mg/L tazobactam was 28.2% (17.5-45.8) and 44.4 (26.6-54.7) for a static and 1log kill respectively at ceftolozane exposures of 33.9-63.3 %fT>MIC of 4 mg/L. The main PDI correlated to effect of tazobactam was time above threshold %fT>CTof 0.5 mg/L tazobactam.

scholarly journals Beta-lactamase inhibitors from laboratory to clinic.

1988 ◽  
Vol 1 (1) ◽  
pp. 109-123 ◽  
Author(s):  
K Bush
Keyword(s):  
Side Effects ◽  
Clavulanic Acid ◽  
Broad Spectrum ◽  
Pathogenic Bacteria ◽  
Defense Mechanism ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Beta Lactamases ◽  
Beta Lactam Antibiotics ◽  
Tract Infections

beta-Lactamases constitute the major defense mechanism of pathogenic bacteria against beta-lactam antibiotics. When the beta-lactam ring of this antibiotic class is hydrolyzed, antimicrobial activity is destroyed. Although beta-lactamases have been identified with clinical failures for over 40 years, enzymes with various abilities to hydrolyze specific penicillins or cephalosporins are appearing more frequently in clinical isolates. One approach to counteracting this resistance mechanism has been through the development of beta-lactamase inactivators. beta-Lactamase inhibitors include clavulanic acid and sulbactam, molecules with minimal antibiotic activity. However, when combined with safe and efficacious penicillins or cephalosporins, these inhibitors can serve to protect the familiar beta-lactam antibiotics from hydrolysis by penicillinases or broad-spectrum beta-lactamases. Both of these molecules eventually inactivate the target enzymes permanently. Although clavulanic acid exhibits more potent inhibitory activity than sulbactam, especially against the TEM-type broad-spectrum beta-lactamases, the spectrum of inhibitory activities are very similar. Neither of these inhibitors acts as a good inhibitor of the cephalosporinases. Clavulanic acid has been most frequently combined with amoxicillin in the orally active Augmentin and with ticarcillin in the parenteral beta-lactam combination Timentin. Sulbactam has been used primarily to protect ampicillin from enzymatic hydrolysis. Sulbactam has been used either in the orally absorbed prodrug form as sultamicillin or as the injectable combination ampicillin-sulbactam. Synergy has been demonstrated for these combinations for most members of the Enterobacteriaceae, although those organisms that produce cephalosporinases are not well inhibited. Synergy has also been observed for Neisseria gonorrhoeae, Haemophilus influenzae, penicillinase-producing Staphylococcus aureus, and anaerobic organisms. These antibiotic combinations have been used clinically to treat urinary tract infections, bone and soft-tissue infections, gonorrhea, respiratory infections, and otitis media. Gastrointestinal side effects have been reported for Augmentin and sultamicillin; most side effects with these agents have been mild. Although combination therapy with beta-lactamase inactivators has been used successfully, the problem of resistance development to two agents must be considered. Induction of cephalosporinases can occur with clavulanic acid. Permeability mutants could arise, especially with added pressure from a second beta-lactam.(ABSTRACT TRUNCATED AT 250 WORDS)

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