Validation du modèle de microporc Yucatan pour les études pharmacocinétiques du ceftriaxone, céfépime, cefpirome et méropénème

Elkhaïli, H.; Levêque, Dominique; Peter, Johannes; Salmon, J.; Salmon, Y.; Kaltenbach, Georges; Cavalier, A; Linger, L.; Pompei, D.; Monteil, H.; Jehl, F.

doi:10.1016/s0399-077x(96)80081-3

Cited by 6 publications

(4 citation statements)

References 12 publications

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“…Cef pirome penetrates the prostate gland, lung, blister fluid and peritoneal fluid reaching con centrations needed for an antibacterial activi ty [21][22][23] The use of continuous infusion for the ad ministration of cephalosporin antibiotic is re turning to favor. We had recently validated the Yucatan micropig as a reliable model for the investigation of cefepime and cefpirome [24], The steady-state concentrations reached in the serum were 16 and 21 mg/1, respectively, enough to obtain a synergistic bactericidal ac tivity when combined with aminoglycosides.…”

Section: Discussionmentioning

confidence: 99%

In vitro Time-Kill Curves of Cefepime and Cef pirome Combined with Amikacin, Gentamicin or Ciprofloxacin against <i>Klebsiella pneumoniae</i> Producing Extended-Spectrum Beta-Lactamase

Elkhaïli¹,

Linger²,

Levêque³

et al. 1997

Chemotherapy

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Extended-spectrum β-lactamases (ESBLs) are found in numerous Enterobacteriaceae, mainly in Klebsiella pneumoniae. We investigated the pharmacodynamics of two new extended-spectrum cephalosporins, cefepime and cefpirome, alone and combined with either amikacin or gentamicin or ciprofloxacin by means of time-kill curves against ESBL-producing, amino-glycoside-resistant K. pneumoniae. When used alone, cefepime (8 and 16 mg/l) resulted in a 2 and 3 log decrease at 6 h, respectively, but at 24 h regrowth occurred. The combination of cefepime (8 mg/l) with amikacin (4 mg/l) resulted in a 4 log decrease at 6 h, but there were no surviving bacteria at 6 h when combined with amikacin (8 mg/l). The combination of cefepime (16 mg/l) with gentamicin (4 mg/l) resulted in a 4 log decrease in 24 h. The antimicrobial combiantion of cefepime (32 mg/l) with ciprofloxacin (2 mg/l) resulted in a 4 log decrease in 24 h. Cefpirome (8 mg/l) induced a 2 log decrease at 4 h; 32 mg/l cefpirome resulted in a 3 log decrease followed by regrowth at 24 h. The regrowth observed in the late phase with cefpirome alone disappeared when combined with aminoglycoside. When cefpirome (32 mg/l) was used in combination with ciprofloxacin (1 mg/l), it resulted in a 4 log decrease in 24 h.

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Section: Discussionmentioning

confidence: 99%

In vitro Time-Kill Curves of Cefepime and Cef pirome Combined with Amikacin, Gentamicin or Ciprofloxacin against <i>Klebsiella pneumoniae</i> Producing Extended-Spectrum Beta-Lactamase

Elkhaïli¹,

Linger²,

Levêque³

et al. 1997

Chemotherapy

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“…The miniature pig is physiologically similar to humans (17) and shows similarities to humans in terms of the pharmacokinetics of several ␤-lactams (cefepime, cefpirome, and meropenem) and other xenobiotics (6). The animal is docile and, because it is small, easy to handle (8).…”

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confidence: 99%

Ex Vivo Pharmacodynamics of Amoxicillin-Clavulanate against β-Lactamase-Producing Escherichia coli in a Yucatan Miniature Pig Model That Mimics Human Pharmacokinetics

Bronner

Murbach

Peter

et al. 2002

Antimicrob Agents Chemother

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The objective of the present study was to investigate the potential bactericidal activity of amoxicillinclavulanate against ␤-lactamase-producing Escherichia coli strains and to elucidate the extent to which enzyme production affects the activity. Six adult Yucatan miniature pigs received a single intravenous dose of 1.1 g of amoxicillin-clavulanate as an intravenous infusion over 30 min. The pharmacokinetic parameters were determined for the serum samples and compared to the published data for humans (2.2-g intravenous dose). The parameters were comparable for the two species, and therefore, the miniature pig constitutes a good model for pharmacodynamic study of amoxicillin-clavulanate. Therefore, the model was used in an ex vivo pharmacodynamic study of amoxicillin-clavulanate against four strains of Escherichia coli producing ␤-lactamases at different levels. The E. coli strains were cultured with serial dilutions (1:2 to 1:256) of the serum samples from the pharmacokinetic study, and the number of surviving bacteria was determined after 1, 3, and 6 h of exposure. Amoxicillin-clavulanate at concentrations less than the MIC and the minimal bactericidal concentration had marked bactericidal potency against the strain that produced low levels of penicillinase. For high-level or intermediate-level ␤-lactamase-producing strains, the existence of a clavulanate concentration threshold of 1.5 to 2 g/ml, below which there was no bactericidal activity, was demonstrated. The index of surviving bacteria showed the existence of mixed concentration-and time-dependent actions of amoxicillin (in the presence of clavulanate) which varied as a function of the magnitude of ␤-lactamase production by the test strains. This study shows the effectiveness of amoxicillin-clavulanate against low-and intermediate-level penicillinase-producing strains of E. coli. These findings are to be confirmed in a miniature pig experimental infection model.Amoxicillin-clavulanate is a combination of a ␤-lactam with a ␤-lactamase inhibitor which restores the potency of amoxicillin against strains producing ␤-lactamases. The potential for the clinical use of such combinations depends in part on the concentrations achieved in serum and tissue after the administration of the usual dosages compared to the MIC for the infecting organism. In particular, it is necessary to obtain concentrations sufficiently inhibitory for the ␤-lactamase in vivo to inactivate the enzymes produced by the bacteria at the infection site.The sensitivity of Escherichia coli to the combination of amoxicillin plus clavulanate depends on the strain's level of ␤-lactamase production. The number of resistant or intermediate-resistant strains is increasing (1); and in E. coli overproduction of chromosomal ␤-lactamases of class C (cephalosporinase) or plasmid enzymes, e.g., TEM-1, TEM-2, and OXA (1,3,23), is the most common mode of ␤-lactam resistance.The aim of the present study was to evaluate the bactericidal potency of amoxicillin-clavulanate in an ex vivo bactericidal model using...

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“…The pharmacokinetics of meropenem and cefpirome given by short infusion and bolus injection, respectively, in the micropig were close to those in humans receiving the same dosage. So, on this basis, the micropig seems to constitute the most reliable model in which to study the pharmacodynamics of these two β‐lactams [12].…”

Section: Discussionmentioning

confidence: 99%

“…Meropenem and cefpirome concentrations in serum were determined by an HPLC technique as previously described [11,12]. Briefly, serum (500 4μL) was deproteinized with 500 μL of acetonitrile in a 5‐mL screwcapped glass tube on a vortex mixer.…”

Section: Animals and Methodsmentioning

confidence: 99%

Pharmacokinetics in vivo and pharmacodynamics ex vivo/in vitro of meropenem and cefpirome in the Yucatan micropig model: continuous infusion versus intermittent injection

Elkhaïli

Peter

Pompei

et al. 1998

Clinical Microbiology and Infection

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OBJECTIVE: To investigate the pharmacodynamic disposition of two recently developed beta-lactam antibiotics, meropenem and cefpirome, in the Yucatan micropig model, and to compare the bactericidal activity of these drugs against bacteria in this in vitro/ex vivo micropig model after administration by both intermittent injection and continuous infusion. METHODS: Cefpirome (1 g) was given to the micropig over a 12-h period by direct intravenous injection and 6-h continuous infusion (500 mg). Meropenem (250 mg) was administered either by 30-min intravenous and 8-h continuous infusion. The two drugs were assayed by HPLC. The pharmacodynamics of these drugs were evaluated by means of (1) serum killing curve against Klebsiella pneumoniae producing extended-spectrum beta-lactamase, stably derepressed Enterobacter cloacae and methicillin-susceptible penicillinase-producing Staphylococcus aureus, and (2) calculations of index of surviving bacteria (ISB). RESULTS: The bactericidal activity of meropenem against K. pneumoniae and E. cloacae in this in vitro/ex vivo model was excellent, with a 4 log decrease at peak concentrations. Meropenem produced a mixed concentration- and time-dependent, killing effect against E. cloacae and K. pneumoniae. The ISB value ranged from 25% to 30% for E. cloacae. With concentrations above MIC for S. aureus (1 mg/L), cefpirome has a time-dependent bactericidal activity, as shown by the ISB ranging from 20% to 80% after 4 h and between 20% and 40% after an 8-h drug exposure. For both antibiotics, the higher concentrations obtained just after intermittent injection had a rapid and strong killing effect against the strains tested, but the trough levels had no bactericidal activity. The continuous infusions produce consistent concentrations of antibiotic that can be maintained above the MIC, and the bactericidal activity of which ranges from 2 to 4 log10 decrease of inoculum. CONCLUSIONS: In the present study the micropig has been shown to be an adequate model for the pharmacodynamic investigation of cefpirome and meropenem. In general, continuous infusion appears to optimize the pharmacodynamic profile of the two tested beta-lactam antibiotics. However, against Gram-negative bacilli, the administration of a loading dose prior to continuous infusion of beta-lactams would eliminate the only potential pharmacokinetic disadvantage of continuous infusion and ensure the rapid onset of antimicrobial activity.

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Validation du modèle de microporc Yucatan pour les études pharmacocinétiques du ceftriaxone, céfépime, cefpirome et méropénème

Cited by 6 publications

References 12 publications

In vitro Time-Kill Curves of Cefepime and Cef pirome Combined with Amikacin, Gentamicin or Ciprofloxacin against <i>Klebsiella pneumoniae</i> Producing Extended-Spectrum Beta-Lactamase

In vitro Time-Kill Curves of Cefepime and Cef pirome Combined with Amikacin, Gentamicin or Ciprofloxacin against <i>Klebsiella pneumoniae</i> Producing Extended-Spectrum Beta-Lactamase

Ex Vivo Pharmacodynamics of Amoxicillin-Clavulanate against β-Lactamase-Producing Escherichia coli in a Yucatan Miniature Pig Model That Mimics Human Pharmacokinetics

Pharmacokinetics in vivo and pharmacodynamics ex vivo/in vitro of meropenem and cefpirome in the Yucatan micropig model: continuous infusion versus intermittent injection

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