Evaluation of antimicrobial regimens in a guinea-pig model of meningitis caused by Pseudomonas aeruginosa

Maiques, José María; Domènech, A.; Cabellos, Carmen; Fernández, A; Ribes, Sandra; Tubau, Fé; Gudiol, Francesc; Viladrich, Pedro F.

doi:10.1016/j.micinf.2006.12.013

Cited by 6 publications

(2 citation statements)

References 27 publications

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“…Studies with rats have shown that DHP-I activity in the brain is negligible (33), approximately 6.4-and 3,000-fold less than in the muscle and the lungs, respectively (17). Since the fraction of cilastatin (16 to 66%) that reaches the cerebrospinal fluid (CSF) is about 3-fold that of meropenem (6 to 20%) in mammals with inflamed meninges (34)(35)(36)(37)(38), the site of infection in this model would have increased M:C ratios with respect to the actual proportions injected subcutaneously. It provides greater protection of meropenem without further increasing the dose of cilastatin and, therefore, is a more sensible model to determine therapeutic equivalence with the mouse.…”

Section: Neutropenic Guinea Pig Soleus Infection Model (Sepsis By Thementioning

confidence: 99%

Even Apparently Insignificant Chemical Deviations among Bioequivalent Generic Antibiotics Can Lead to Therapeutic Nonequivalence: the Case of Meropenem

Agudelo

Rodríguez

Peláez

et al. 2014

Antimicrob Agents Chemother

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e Several studies with animal models have demonstrated that bioequivalence of generic products of antibiotics like vancomycin, as currently defined, do not guarantee therapeutic equivalence. However, the amounts and characteristics of impurities and degradation products in these formulations do not violate the requirements of the U.S. Pharmacopeia (USP). Here, we provide experimental data with three generic products of meropenem that help in understanding how these apparently insignificant chemical differences affect the in vivo efficacy. Meropenem generics were compared with the innovator in vitro by microbiological assay, susceptibility testing, and liquid chromatography/mass spectrometry (LC/MS) analysis and in vivo with the neutropenic guinea pig soleus infection model (Pseudomonas aeruginosa) and the neutropenic mouse thigh (P. aeruginosa), brain (P. aeruginosa), and lung (Klebisella pneumoniae) infection models, adding the dihydropeptidase I (DHP-I) inhibitor cilastatin in different proportions to the carbapenem. We found that the concentration and potency of the active pharmaceutical ingredient, in vitro susceptibility testing, and mouse pharmacokinetics were identical for all products; however, two generics differed significantly from the innovator in the guinea pig and mouse models, while the third generic was therapeutically equivalent under all conditions. Trisodium adducts in a bioequivalent generic made it more susceptible to DHP-I hydrolysis and less stable at room temperature, explaining its therapeutic nonequivalence. We conclude that the therapeutic nonequivalence of generic products of meropenem is due to greater susceptibility to DHP-I hydrolysis. These failing generics are compliant with USP requirements and would remain undetectable under current regulations.

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Section: Neutropenic Guinea Pig Soleus Infection Model (Sepsis By Thementioning

confidence: 99%

Even Apparently Insignificant Chemical Deviations among Bioequivalent Generic Antibiotics Can Lead to Therapeutic Nonequivalence: the Case of Meropenem

Agudelo

Rodríguez

Peláez

et al. 2014

Antimicrob Agents Chemother

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“…(a) β-Lactams with aminoglycosides (Peterson et al 1984 ;Rusnak et al 1984 ;Bayer et al 1985a ;Mordenti et al 1985 ;Johnson 1985 ;Chin et al 1986 ;Chadwick et al 1986 ;Moody et al 1987 ;Gordin et al 1987 ;Gerber et al 1989 ;Ulrich et al 1989 ;Pefanis et al 1993 ;Mimoz et al 1999 ;Robaux et al 2001 ;Placensia et al 2007 ;Chan et al 2006 ;Maiques et al 2007 ;Yuan et al 2010 ); although there are exceptions (Ulrich et al 1989 ; Pefanis et al 1993 ;Robaux et al 2001 ;Johnson et al 1987 ;Chusid et al 1983 ;Kemmerich et al 1986 ;Thauvin et al 1989 ;Johnson and Thompson 1986 ;Navas et al 2004 ), many of which were strain dependent and/or were seen in endocarditis models. (b) β-Lactams with fl uoroquinolones (Ulrich et al 1989 ;Johnson et al 1987 ;Placensia et al 2007 ), with some exceptions (Ulrich et al 1989 ;Thauvin et al 1989 ).…”

Section: In Vitro Pharmacodynamic Modelsmentioning

confidence: 99%

Drug–Drug Combinations

Turnidge

2013

Fundamentals of Antimicrobial Pharmacokinetics and Pharmacodynamics

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Antimicrobial combination therapy has a long history. The potential for synergy between two antimicrobial agents has been sought using in vitro techniques such as disk approximation, checkerboard titration, in vitro killing experiments with fi xed drug concentrations, through the use of in vitro pharmacodynamic models, through animal models, and through retrospective and prospective clinical studies. The most widely examined combinations are those that include aminoglycosides, especially for the treatment of serious Pseudomonas aeruginosa infections, and for the management of enterococcal and staphylococcal endocarditis. The in vitro and animal studies of P. aeruginosa support the concept that combinations of aminoglycosides with β-lactams improve effi cacy and outcomes. Some models suggest that the mechanism of improved effi cacy relates less to synergy and more the prevention of the selection of aminoglycoside-resistant mutants. However, human clinical studies to date have failed to demonstrate convincingly that there are better outcomes with combination therapy in terms of effi cacy or the prevention of resistance emergence. For endocarditis, there has been strong evidence accumulated for combination therapy enterococcal endocarditis using in vitro and animal models, although there are no randomised clinical data to confi rm these. Data supporting the use of combination in staphylococcal therapy has been less robust, and Panton-valentine leukocidin producing S. aureusCell-wall active agent + clindamycin or linezolid the role of combination treatment for this indication is now in question. Ultimately, an in vitro or animal model of the pharmacodynamic interaction of drug classes that can be shown to predict clinical outcomes is still required. Such a model does not currently exist.

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Experimental study of meropenem in the therapy of cephalosporin-susceptible and -resistant pneumococcal meningitis

Force

Taberner

Cabellos

et al. 2008

Eur J Clin Microbiol Infect Dis

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Meropenem is a carbapenem antibiotic that is highly active against the pathogens causing meningitis. Results with meropenem in the experimental rabbit model of penumococcal meningitis have been controversial, and the possible role of renal dehydropeptidase I in meropenem efficacy has been suggested. The aim of this study was to determine the efficacy of meropenem in two meningitis models and the possible influence of the animal model over results. Two strains of Streptococcus pneumoniae with different susceptibility to beta-lactams have been used in a guinea pig model and the classical rabbit meningitis model. Meropenem was bactericidal at 6 h in the guinea pig model against both strains with a reduction of >4 log ufc/ml. In the rabbit model it was bactericidal at 6 h against the susceptible strain, but against the resistant 3/8 therapeutical failures were recorded at 6 h, being bactericidal at 24 h. In conclusion, meropenem has shown bactericidal activity in both experimental models. This work emphasises the importance of an adequate election of the animal model for the appropriate development of studies of antimicrobial efficacy. We believe that guinea pig should be considered the best choice among laboratory animal species when assessing meropenem efficacy.

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Evaluation of antimicrobial regimens in a guinea-pig model of meningitis caused by Pseudomonas aeruginosa

Cited by 6 publications

References 27 publications

Even Apparently Insignificant Chemical Deviations among Bioequivalent Generic Antibiotics Can Lead to Therapeutic Nonequivalence: the Case of Meropenem

Even Apparently Insignificant Chemical Deviations among Bioequivalent Generic Antibiotics Can Lead to Therapeutic Nonequivalence: the Case of Meropenem

Drug–Drug Combinations

Experimental study of meropenem in the therapy of cephalosporin-susceptible and -resistant pneumococcal meningitis

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