The Experts below are selected from a list of 165 Experts worldwide ranked by ideXlab platform
M. Struelens - One of the best experts on this subject based on the ideXlab platform.
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In vitro activity of Temocillin against prevalent extended-spectrum beta-lactamases producing Enterobacteriaceae from Belgian intensive care units
European Journal of Clinical Microbiology & Infectious Diseases, 2007Co-Authors: Y. Glupczynski, T.-d. Huang, C. Berhin, G. Claeys, M. Delmée, L. Ide, G. Ieven, D. Pierard, H. Rodriguez-villalobos, M. StruelensAbstract:Temocillin is a narrow spectrum penicillin with high stability to most β-lactamases including AmpC types and extended-spectrum types (ESBLs). We have analysed its in vitro activity against 652 clinical isolates of Enterobacteriaceae prospectively collected from patients hospitalised in intensive care units at seven different university hospitals in Belgium in 2005. Strains were screened for ESBL production using cefotaxime and ceftazidime screen agar plates and by double ESBL E-tests. The MIC of Temocillin and of five comparators was determined using the E-test method. ESBLs were characterized at one central laboratory by isoelectric focusing, PCR for bla genes of the SHV, TEM, and CTX-M families, and by DNA sequencing. The prevalence of ESBL-producing Enterobacteriaceae averaged 11.8% and ranged between 3.0 and 29% in the different hospitals. Meropenem exhibited the highest in vitro activity overall (mode MIC 0.064 μg; MIC_90; 0.19 μg/ml), whereas ceftazidime (MIC_90 > 256 μg/ml) and ciprofloxacin (MIC_90 > 32 μg/ml) scored the worst. Temocillin was active against more than 90% of the isolates including most AmpC- and ESBL-producing isolates. These data indicate the well preserved activity of Temocillin over the years against Enterobacteriaceae and show the wide variation in prevalence of ESBL-producing Enterobacteriaceae isolates in Belgian intensive care units. Prospective clinical studies are, however, needed to validate the usefulness of Temocillin in the treatment of microbiologically documented infections caused by ESBL- and/or AmpC- overproducing nosocomial Enterobacteriaceae pathogens.
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in vitro activity of Temocillin against prevalent extended spectrum beta lactamases producing enterobacteriaceae from belgian intensive care units
European Journal of Clinical Microbiology & Infectious Diseases, 2007Co-Authors: Youri Glupczynski, T.-d. Huang, C. Berhin, G. Claeys, M. Delmée, L. Ide, G. Ieven, D. Pierard, Hector Rodriguezvillalobos, M. StruelensAbstract:Temocillin is a narrow spectrum penicillin with high stability to most beta-lactamases including AmpC types and extended-spectrum types (ESBLs). We have analysed its in vitro activity against 652 clinical isolates of Enterobacteriaceae prospectively collected from patients hospitalised in intensive care units at seven different university hospitals in Belgium in 2005. Strains were screened for ESBL production using cefotaxime and ceftazidime screen agar plates and by double ESBL E-tests. The MIC of Temocillin and of five comparators was determined using the E-test method. ESBLs were characterized at one central laboratory by isoelectric focusing, PCR for bla genes of the SHV, TEM, and CTX-M families, and by DNA sequencing. The prevalence of ESBL-producing Enterobacteriaceae averaged 11.8% and ranged between 3.0 and 29% in the different hospitals. Meropenem exhibited the highest in vitro activity overall (mode MIC 0.064 microg; MIC(90); 0.19 microg/ml), whereas ceftazidime (MIC(90) > 256 microg/ml) and ciprofloxacin (MIC(90) > 32 microg/ml) scored the worst. Temocillin was active against more than 90% of the isolates including most AmpC- and ESBL-producing isolates. These data indicate the well preserved activity of Temocillin over the years against Enterobacteriaceae and show the wide variation in prevalence of ESBL-producing Enterobacteriaceae isolates in Belgian intensive care units. Prospective clinical studies are, however, needed to validate the usefulness of Temocillin in the treatment of microbiologically documented infections caused by ESBL- and/or AmpC- overproducing nosocomial Enterobacteriaceae pathogens.
Bruno Fantin - One of the best experts on this subject based on the ideXlab platform.
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Temocillin as an alternative treatment for acute bacterial cholangitis: a retrospective microbiology susceptibility-based study of 140 episodes
European Journal of Clinical Microbiology & Infectious Diseases, 2021Co-Authors: Sylvain Chawki, Aurélien Sokal, Marion Duprilot, Amandine Henry, Véronique Leflon-guibout, Marie-hélène Nicolas-chanoine, Bruno Fantin, Victoire LastoursAbstract:With rising antibiotic resistance, alternatives to carbapenems are needed for acute cholangitis (AC). Temocillin reaches high biliary concentrations with limited impact on microbiota. We retrospectively included 140 AC episodes and assessed the efficacy of Temocillin using microbiology susceptibility testing from blood cultures. Considering all bacteria collected by episode, resistance to Temocillin, PIP/TAZ and 3GC occurred in 27/140 (26%), 32 (22.8%) and 31 (22%) episodes, respectively ( p = 0.7). After documentation, Temocillin could have spared PIP/TAZ or carbapenems in 14/26 and 4/11 episodes. Temocillin may constitute an alternative treatment after microbiological documentation by sparing carbapenems and/or PIP/TAZ, but not as an empirical therapeutic option.
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Temocillin breakpoints in pyelonephritis evaluation in a murine model due to esbl producing escherichia coli clinical isolates
Journal of Antimicrobial Chemotherapy, 2019Co-Authors: Kevin Alexandre, Bruno Fantin, Anais Soares, F Chau, F Caron, Manuel EtienneAbstract:BACKGROUND Due to a spectrum restricted to Enterobacteriaceae and stability against ESBL and AmpC enzymes, Temocillin is of major interest for the treatment of pyelonephritis. But there are still uncertainties about the optimal regimen and clinical breakpoints. OBJECTIVES To study in a murine model of pyelonephritis the activity of Temocillin against Escherichia coli isolates with different MICs in order to evaluate clinical breakpoints. METHODS Four clinical uropathogenic E. coli isolates with Temocillin MICs of 8 mg/L (Ec8), 16 mg/L (Ec16), 32 mg/L (Ec32) and 64 mg/L (Ec64) were evaluated. Antibiotic 24 h T>MIC achieved in humans was reproduced in mice with either intravenous Temocillin (2 g q12h or 2 g q8h) or intravenous imipenem (1 g q8h). Efficacy was assessed by bacterial count in kidneys. RESULTS Compared with controls, Temocillin at 2 g q12h was highly efficient against Ec8 (-3.32 log10 cfu/g and negative cultures in 93% of mice; P < 0.001); imipenem gave similar results. Temocillin at 2 g q12h also induced high reduction of bacterial count against Ec16 (-2.92 log10 cfu/g; P < 0.001), albeit cultures were negative in only 48% of mice. In contrast, no significant effect was observed in mice infected by Ec32 (-0.01 log10 cfu/g; P = 0.981) or Ec64 (-0.55 log10 cfu/g; P = 0.523). Even Temocillin at 2 g q8h failed to control Ec32 infection (-1.55 log10 cfu/g; P = 0.197). CONCLUSIONS This model suggests a clinical breakpoint up to 16 mg/L for non-severe pyelonephritis treated with Temocillin at 2 g q12h, a value consistent with the few previous available data.
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Pharmacokinetics and Pharmacodynamics of Temocillin
Clinical Pharmacokinetics, 2018Co-Authors: Kevin Alexandre, Bruno FantinAbstract:Temocillin, a 6-α-methoxy derivative of ticarcillin, is a forgotten antibiotic that has recently been rediscovered, and issues about clinical breakpoints and optimal therapeutic regimens are still ongoing. Temocillin spectrum is almost restricted to Enterobacteriaceae . The addition of the α-methoxy moiety on ticarcillin confers resistance to hydrolysis by Ambler classes A and C β-lactamases (extended spectrum β-lactamases, Klebsiella pneumoniae carbapenemase and AmpC hyperproduced enzymes). Temocillin is bactericidal, and the effect of inoculum size on its activity is relatively mild. The proportion of spontaneous resistant mutants in vitro to Temocillin is low, as found in vivo. After intravenous infusion, Temocillin showed a prolonged elimination half-life of approximately 5 h. The percentage of protein binding of Temocillin is high (approximately 80%), and is concentration-dependent. Temocillin clearance is mainly renal, and urinary recovery is high, ranging from 72 to 82% after 24 h. Furthermore, the penetration of Temocillin into bile and peritoneal fluid is high, but poor into cerebrospinal fluid. The cumulative percentage of a 24-h period during which the free drug concentration exceeds the minimum inhibitory concentration (fT > MIC) at steady-state pharmacokinetic conditions seems to be the best pharmacokinetic/pharmacodynamic (PK/PD) index correlating with Temocillin efficacy. An fT > MIC of 40–50% is associated with antibacterial effect and survival in vivo. Monte Carlo simulations performed in critically ill patients showed that the 2 g every 12 h and 2 g every 8 h regimens provide a 95% probability of target attainment of 40% fT > MIC up to an MIC of 8 mg/L. In less severely ill patients or in specific foci of infection, such as urinary tract infection, a 4 g daily regimen should be adequate for strains with Temocillin MIC up to 16 mg/L. Data regarding actual wild-type MIC distribution, clinical efficacy, PK profiling in volunteers or patients, and PD targets are scarce, and further studies are required to support appropriate dosing recommendations and determination of clinical breakpoints.
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activity of Temocillin in a lethal murine model of infection of intra abdominal origin due to kpc producing escherichia coli
Journal of Antimicrobial Chemotherapy, 2016Co-Authors: K Alexandre, Bruno Fantin, Vincent Cattoir, F Chau, Francois Guerin, L Massias, A LefortAbstract:OBJECTIVES: Temocillin is a 6-α-methoxy derivative of ticarcillin that shows in vitro activity against Enterobacteriaceae producing Klebsiella pneumoniae carbapenemase (KPC). Our objective was to assess in vivo Temocillin activity against KPC-producing Escherichia coli. METHODS: Isogenic derivatives of the WT E. coli CFT073 producing KPC-2, KPC-3 or OXA-48 were constructed. An experimental murine model of intra-abdominal infection with sepsis was used. Mice were treated subcutaneously with Temocillin 200 mg/kg every 2 h for 24 h, reproducing the duration of time that the free serum concentration of Temocillin exceeded the MIC in humans with a regimen of 2 g every 12 h or 2 g every 8 h. Blood, peritoneal fluid (PF) and spleen were collected; 24 h survival and sterility rates were assessed. RESULTS: Temocillin MICs were 8, 16, 32, and 256 mg/L for the susceptible strain and KPC-2-, KPC-3-, and OXA-48-producing strains, respectively. In mice treated with Temocillin, significant bacterial reduction was obtained in PF, blood, and spleen for the susceptible strain and KPC-2- and KPC-3-producing strains (P < 0.001) but not for the OXA-48-producing strain. Sterility rates in PF were 53%, 10%, 0% and 0% (P < 0.001) and sterility rates in blood were 77%, 40%, 3% and 0% (P < 0.001), while survival rates were 97%, 97%, 57%, 0% (P < 0.001) for mice infected with the susceptible strain and KPC-2-, KPC-3- and OXA-48-producing strains, respectively. CONCLUSIONS: In a lethal-infection model with bacteraemia from intra-abdominal origin, Temocillin retained significant activity in PF, blood and spleen and prevented death in mice by effectively working against KPC-producing E. coli with Temocillin MICs ≤16 mg/L.
Vincent Cattoir - One of the best experts on this subject based on the ideXlab platform.
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Temocillin susceptibility among Enterobacterales strains recovered from blood culture in France.
Diagnostic microbiology and infectious disease, 2021Co-Authors: Eric Farfour, Anne-gaelle Si Larbi, Vincent Cattoir, Stéphane Corvec, T. Guillard, Antoine Grillon, Christophe Isnard, Audrey Mérens, Nicolas Degand, Typhaine Billard-pomaresAbstract:Temocillin is used for several years in some European countries but, only since 2015 in France. We assessed the susceptibility of Enterobacterales strains isolated from blood culture 1 year before (2014) and 2 years after (2017) its use in France. 1,387 strains were included by 17 clinical laboratories located throughout France: 363 in 2014 and 1,024 in 2017. The rate of resistance to Temocillin was 4.6% and 26.7% in 3rd generation cephalosporin (3GC) susceptible and resistant strains respectively. Cephalosporinase-overproducer (COPE) strains were significantly more resistant to Temocillin (37.7%) than ESBL-producer (ESBL-PE) (23.5%) (P < 0.01). The rate of Temocillin resistance was correlated to the number of inactive beta-lactams. The rate of resistance to Temocillin trend to increase from 13.9% in 2014 to 23.9% in 2017 (P < 0.01). Temocillin remains highly active against Enterobacterales but the trend in resistance should be assessed over time.
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Temocillin susceptibility among enterobacterales strains recovered from blood culture in france
Diagnostic Microbiology and Infectious Disease, 2021Co-Authors: Eric Farfour, Anne-gaelle Si Larbi, Vincent Cattoir, Stéphane Corvec, T. Guillard, Antoine Grillon, Christophe Isnard, Audrey Mérens, Nicolas Degand, Typhaine BillardpomaresAbstract:Abstract Temocillin is used for several years in some European countries but, only since 2015 in France. We assessed the susceptibility of Enterobacterales strains isolated from blood culture 1 year before (2014) and 2 years after (2017) its use in France. 1,387 strains were included by 17 clinical laboratories located throughout France: 363 in 2014 and 1,024 in 2017. The rate of resistance to Temocillin was 4.6% and 26.7% in 3rd generation cephalosporin (3GC) susceptible and resistant strains respectively. Cephalosporinase-overproducer (COPE) strains were significantly more resistant to Temocillin (37.7%) than ESBL-producer (ESBL-PE) (23.5%) (P
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activity of fosfomycin alone or combined with Temocillin in vitro and in a murine model of peritonitis due to kpc 3 or oxa 48 producing escherichia coli
Journal of Antimicrobial Chemotherapy, 2018Co-Authors: M Berleur, Vincent Cattoir, F Chau, Francois Guerin, L Massias, J Poujade, B Fantin, V De LastoursAbstract:Background - Alternative therapeutic regimens are urgently needed against carbapenemase-producing Enterobacteriaceae. Fosfomycin often remains active against KPC and OXA-48 producers, but emergence of resistance is a major limitation. Our aim was to determine whether the association of Temocillin with fosfomycin might be useful to treat KPC- or OXA-48-producing Escherichia coli infections. Methods - Isogenic derivatives of E. coli CFT073 with blaKPC-3- or blaOXA-48-harbouring plasmids (named CFT073-KPC-3 and CFT073-OXA-48, respectively) were used. The addition of Temocillin to fosfomycin was tested using the chequerboard method and time-kill curves as well as in a fatal peritonitis murine model. Mice were treated for 24 h with fosfomycin alone or in combination with Temocillin. Bacterial loads, before and after treatment, were determined in the peritoneal fluid and fosfomycin-resistant mutants were detected. Results - Temocillin MICs were 8, 32 and 256 mg/L for CFT073 (WT), CFT073-KPC-3 and CFT073-OXA-48, respectively. Fosfomycin MIC was 0.5 mg/L for all strains. The chequerboard experiments demonstrated synergy for all three strains. In time-kill curves, combining Temocillin with fosfomycin was synergistic, bactericidal and prevented emergence of resistance for CFT073-pTOPO and CFT073-KPC-3, but not CFT073-OXA-48. In vivo, for the three strains, bacterial counts were lower in peritoneal fluid with the combination compared with fosfomycin alone (P < 0.001) and inhibited growth of resistant mutants in all cases. Conclusions - The combination of fosfomycin and Temocillin demonstrated a benefit in vitro and in vivo against E. coli strains producing KPC-3 or OXA-48-type carbapenemases. This combination prevented the emergence of fosfomycin resistance and proved to be more bactericidal than fosfomycin alone.
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activity of Temocillin in a lethal murine model of infection of intra abdominal origin due to kpc producing escherichia coli
Journal of Antimicrobial Chemotherapy, 2016Co-Authors: K Alexandre, Bruno Fantin, Vincent Cattoir, F Chau, Francois Guerin, L Massias, A LefortAbstract:OBJECTIVES: Temocillin is a 6-α-methoxy derivative of ticarcillin that shows in vitro activity against Enterobacteriaceae producing Klebsiella pneumoniae carbapenemase (KPC). Our objective was to assess in vivo Temocillin activity against KPC-producing Escherichia coli. METHODS: Isogenic derivatives of the WT E. coli CFT073 producing KPC-2, KPC-3 or OXA-48 were constructed. An experimental murine model of intra-abdominal infection with sepsis was used. Mice were treated subcutaneously with Temocillin 200 mg/kg every 2 h for 24 h, reproducing the duration of time that the free serum concentration of Temocillin exceeded the MIC in humans with a regimen of 2 g every 12 h or 2 g every 8 h. Blood, peritoneal fluid (PF) and spleen were collected; 24 h survival and sterility rates were assessed. RESULTS: Temocillin MICs were 8, 16, 32, and 256 mg/L for the susceptible strain and KPC-2-, KPC-3-, and OXA-48-producing strains, respectively. In mice treated with Temocillin, significant bacterial reduction was obtained in PF, blood, and spleen for the susceptible strain and KPC-2- and KPC-3-producing strains (P < 0.001) but not for the OXA-48-producing strain. Sterility rates in PF were 53%, 10%, 0% and 0% (P < 0.001) and sterility rates in blood were 77%, 40%, 3% and 0% (P < 0.001), while survival rates were 97%, 97%, 57%, 0% (P < 0.001) for mice infected with the susceptible strain and KPC-2-, KPC-3- and OXA-48-producing strains, respectively. CONCLUSIONS: In a lethal-infection model with bacteraemia from intra-abdominal origin, Temocillin retained significant activity in PF, blood and spleen and prevented death in mice by effectively working against KPC-producing E. coli with Temocillin MICs ≤16 mg/L.
Francoise Van Bambeke - One of the best experts on this subject based on the ideXlab platform.
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thrice weekly Temocillin administered after each dialysis session is appropriate for the treatment of serious gram negative infections in haemodialysis patients
International Journal of Antimicrobial Agents, 2015Co-Authors: Stefaan J Vandecasteele, Ana Miranda C Bastos, Arnaud Capron, Anne Spinewine, Paul M Tulkens, Francoise Van BambekeAbstract:In patients with end-stage renal disease (ESRD) treated with intermittent haemodialysis, a limited number of antibiotics have been studied for their suitability for parenteral administration after dialysis sessions only in a thrice-weekly regimen. Temocillin is a β-lactam antibiotic with a long half-live and enhanced activity against most Gram-negative bacteria, including extended-spectrum β-lactamase-producers, thus making it an ideal candidate for use in this setting. This study aimed to evaluate the reliability of thrice-weekly parenteral Temocillin in haemodialysis patients by characterising the pharmacokinetics of total and free Temocillin. Free and total Temocillin concentrations were determined with a validated HPLC method in 448 samples derived from 48 administration cycles in 16 patients with ESRD treated with intermittent haemodialysis and Temocillin. Pharmacokinetics were non-linear partly due to saturation in protein binding. Median clearance and half-life for the free drug during intradialysis and interdialysis periods were 113 mL/min vs. 26 mL/min and 3.6 h vs. 24 h, respectively, with dialysis extracting approximately one-half of the residual concentration. The free Temocillin concentration remained >16 mg/L (MIC90 threshold for most Enterobacteriaceae) during 48%, 67% and 71% of the dosing interval for patients receiving 1 g q24h, 2 g q48h and 3 g q72h, respectively, suggesting appropriate exposure for the two latter therapeutic schemes. Temocillin administered on dialysis days only in a dosing schedule of 2 g q48h and 3 g q72h is appropriate for the treatment of serious and/or resistant Gram-negative infections in patients with ESRD undergoing intermittent haemodialysis. These doses are higher than those previously recommended.
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validation of a hplc ms ms assay for the determination of total and unbound concentration of Temocillin in human serum
Clinical Biochemistry, 2015Co-Authors: Perrin Ngougni Pokem, Ana Miranda C Bastos, Paul M Tulkens, Francoise Van Bambeke, Pierre Wallemacq, Arnaud CapronAbstract:OBJECTIVES: The aim of this study was to develop and validate a HPLC-MS/MS assay to determine total and unbound concentrations of Temocillin in serum samples. DESIGN AND METHODS: Methanolic protein precipitation and ultrafiltration were used for total and unbound concentration extraction, respectively. Extract was injected into a LC-MS/MS system. Reversed phase chromatography was performed on a phenyl grafted column in gradient mode. Temocillin and internal standard (ticarcillin) were identified in positive electrospray ionization mode using ion transitions of m/z 415.34>339.1 and 385.31>160.3, respectively. RESULTS: Temocillin total and unbound concentration quantification assays were linear over concentrations ranging from 1 to 500mg/L and from 0.5 to 300mg/L, respectively. Both assays presented acceptable intra and inter-assay precision and accuracy <13.9%. Limits of quantification and detection were of 1 and 0.10mg/L, and 0.5 and 0.05mg/L for total and unbound concentration respectively. Total Temocillin concentration recovery ranged from 85.80 to 99.40%. Temocillin ion suppression effect was <36.2 % in both assays. CONCLUSION: The method described is fast, sensitive and selective, with no interferences. This method may be used for both pharmacokinetic studies and therapeutic drug monitoring purposes.
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development and validation of a high performance liquid chromatography assay for the determination of Temocillin in serum of haemodialysis patients
Journal of Pharmaceutical and Biomedical Analysis, 2014Co-Authors: Ana Miranda C Bastos, Stefaan J Vandecasteele, Anne Spinewine, Paul M Tulkens, Francoise Van BambekeAbstract:Therapeutic drug monitoring of β-lactams can be useful for the optimization of therapy, especially when little reference data exist on actual pharmacokinetic profiles such as in patients undergoing haemodialysis. There is no reported validated method for Temocillin assay in serum samples, and preliminary studies evidenced potential for interferences by acidic metabolites and co-administered drugs in patients with advanced kidney failure. This paper describes a fully validated method for the determination of Temocillin in human serum, and its applicability in haemodialysis patients. Temocillin was extracted from human serum by a solid phase extraction methodology, and then assayed by reversed-phase HPLC with UV-detection. The method was validated according to the accuracy profile methodology, using total error to verify the trueness, precision and overall accuracy. It showed high specificity and precision and was accurate in the concentration range of 5-400 mg/L. LOD and LOQ were 1.2 and 5 mg/L, respectively. No interference with 30 co-administered drugs was evidenced. The method was successfully applied to clinical samples from haemodialysis patients, showing a high degree of dialysability of Temocillin.
L Massias - One of the best experts on this subject based on the ideXlab platform.
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activity of fosfomycin alone or combined with Temocillin in vitro and in a murine model of peritonitis due to kpc 3 or oxa 48 producing escherichia coli
Journal of Antimicrobial Chemotherapy, 2018Co-Authors: M Berleur, Vincent Cattoir, F Chau, Francois Guerin, L Massias, J Poujade, B Fantin, V De LastoursAbstract:Background - Alternative therapeutic regimens are urgently needed against carbapenemase-producing Enterobacteriaceae. Fosfomycin often remains active against KPC and OXA-48 producers, but emergence of resistance is a major limitation. Our aim was to determine whether the association of Temocillin with fosfomycin might be useful to treat KPC- or OXA-48-producing Escherichia coli infections. Methods - Isogenic derivatives of E. coli CFT073 with blaKPC-3- or blaOXA-48-harbouring plasmids (named CFT073-KPC-3 and CFT073-OXA-48, respectively) were used. The addition of Temocillin to fosfomycin was tested using the chequerboard method and time-kill curves as well as in a fatal peritonitis murine model. Mice were treated for 24 h with fosfomycin alone or in combination with Temocillin. Bacterial loads, before and after treatment, were determined in the peritoneal fluid and fosfomycin-resistant mutants were detected. Results - Temocillin MICs were 8, 32 and 256 mg/L for CFT073 (WT), CFT073-KPC-3 and CFT073-OXA-48, respectively. Fosfomycin MIC was 0.5 mg/L for all strains. The chequerboard experiments demonstrated synergy for all three strains. In time-kill curves, combining Temocillin with fosfomycin was synergistic, bactericidal and prevented emergence of resistance for CFT073-pTOPO and CFT073-KPC-3, but not CFT073-OXA-48. In vivo, for the three strains, bacterial counts were lower in peritoneal fluid with the combination compared with fosfomycin alone (P < 0.001) and inhibited growth of resistant mutants in all cases. Conclusions - The combination of fosfomycin and Temocillin demonstrated a benefit in vitro and in vivo against E. coli strains producing KPC-3 or OXA-48-type carbapenemases. This combination prevented the emergence of fosfomycin resistance and proved to be more bactericidal than fosfomycin alone.
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Activity of fosfomycin alone or combined with Temocillin in vitro and in a murine model of peritonitis due to KPC-3- or OXA-48-producing Escherichia coli
Journal of Antimicrobial Chemotherapy, 2018Co-Authors: M Berleur, L Massias, J Poujade, B Fantin, F Guérin, F Chau, V Cattoir, V De LastoursAbstract:Background - Alternative therapeutic regimens are urgently needed against carbapenemase-producing Enterobacteriaceae. Fosfomycin often remains active against KPC and OXA-48 producers, but emergence of resistance is a major limitation. Our aim was to determine whether the association of Temocillin with fosfomycin might be useful to treat KPC- or OXA-48-producing Escherichia coli infections. Methods - Isogenic derivatives of E. coli CFT073 with blaKPC-3- or blaOXA-48-harbouring plasmids (named CFT073-KPC-3 and CFT073-OXA-48, respectively) were used. The addition of Temocillin to fosfomycin was tested using the chequerboard method and time-kill curves as well as in a fatal peritonitis murine model. Mice were treated for 24 h with fosfomycin alone or in combination with Temocillin. Bacterial loads, before and after treatment, were determined in the peritoneal fluid and fosfomycin-resistant mutants were detected. Results - Temocillin MICs were 8, 32 and 256 mg/L for CFT073 (WT), CFT073-KPC-3 and CFT073-OXA-48, respectively. Fosfomycin MIC was 0.5 mg/L for all strains. The chequerboard experiments demonstrated synergy for all three strains. In time-kill curves, combining Temocillin with fosfomycin was synergistic, bactericidal and prevented emergence of resistance for CFT073-pTOPO and CFT073-KPC-3, but not CFT073-OXA-48. In vivo, for the three strains, bacterial counts were lower in peritoneal fluid with the combination compared with fosfomycin alone (P
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activity of Temocillin in a lethal murine model of infection of intra abdominal origin due to kpc producing escherichia coli
Journal of Antimicrobial Chemotherapy, 2016Co-Authors: K Alexandre, Bruno Fantin, Vincent Cattoir, F Chau, Francois Guerin, L Massias, A LefortAbstract:OBJECTIVES: Temocillin is a 6-α-methoxy derivative of ticarcillin that shows in vitro activity against Enterobacteriaceae producing Klebsiella pneumoniae carbapenemase (KPC). Our objective was to assess in vivo Temocillin activity against KPC-producing Escherichia coli. METHODS: Isogenic derivatives of the WT E. coli CFT073 producing KPC-2, KPC-3 or OXA-48 were constructed. An experimental murine model of intra-abdominal infection with sepsis was used. Mice were treated subcutaneously with Temocillin 200 mg/kg every 2 h for 24 h, reproducing the duration of time that the free serum concentration of Temocillin exceeded the MIC in humans with a regimen of 2 g every 12 h or 2 g every 8 h. Blood, peritoneal fluid (PF) and spleen were collected; 24 h survival and sterility rates were assessed. RESULTS: Temocillin MICs were 8, 16, 32, and 256 mg/L for the susceptible strain and KPC-2-, KPC-3-, and OXA-48-producing strains, respectively. In mice treated with Temocillin, significant bacterial reduction was obtained in PF, blood, and spleen for the susceptible strain and KPC-2- and KPC-3-producing strains (P < 0.001) but not for the OXA-48-producing strain. Sterility rates in PF were 53%, 10%, 0% and 0% (P < 0.001) and sterility rates in blood were 77%, 40%, 3% and 0% (P < 0.001), while survival rates were 97%, 97%, 57%, 0% (P < 0.001) for mice infected with the susceptible strain and KPC-2-, KPC-3- and OXA-48-producing strains, respectively. CONCLUSIONS: In a lethal-infection model with bacteraemia from intra-abdominal origin, Temocillin retained significant activity in PF, blood and spleen and prevented death in mice by effectively working against KPC-producing E. coli with Temocillin MICs ≤16 mg/L.
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activity of Temocillin in a murine model of urinary tract infection due to escherichia coli producing or not producing the esbl ctx m 15
Journal of Antimicrobial Chemotherapy, 2015Co-Authors: F Chau, J F Soubirou, B Rossi, Camille Couffignal, Etienne Ruppe, L MassiasAbstract:OBJECTIVES Temocillin is a 6α-methoxy derivative of ticarcillin that is resilient to ESBLs. Prospective data about its in vivo activity remain scarce. Our aims were: (i) to evaluate the activity of Temocillin in a urinary tract infection (UTI) model due to ESBL-producing Escherichia coli and compare it with that of imipenem; and (ii) to define in vivo susceptibility breakpoints. METHODS Mice were infected with a susceptible E. coli CFT073-RR or its transconjugant (CFT073-RR Tc) harbouring a blaCTX-M-15-carrying plasmid, using an ascending UTI model. Therapeutic regimens were chosen in order to reproduce percentage of time of free drug concentrations above MIC (fT>MIC) obtained in humans with standard regimens of Temocillin (200 mg/kg every 2 h for 2 g every 12 h) or imipenem (100 mg/kg every 2 h for 1 g every 8 h). Additional regimens of Temocillin (200 mg/kg every 4 and 6 h) with reduced fT>MIC were studied. RESULTS MICs of Temocillin and imipenem were 4/8 and 0.5/0.5 mg/L, for CFT073-RR and CFT073-RR Tc, respectively. In vivo, when given every 2 h (fT>MIC = 82% and 70%), Temocillin was bactericidal and as effective as imipenem in kidneys against both strains without selecting resistant mutants. Temocillin remained active even when given every 4 h, generating an fT>MIC of 41% and 35%, which corresponded to a breakpoint of 16 mg/L in humans with the standard regimen. CONCLUSIONS Our observations support the consideration of a standard regimen of Temocillin as an alternative to carbapenems for the treatment of UTI due to CTX-M-producing E. coli strains with an MIC of 16 mg/L or less.
