Correlation between in vitro and in vivo activity of antimicrobial agents against gram-negative bacilli in a murine infection model

Fantin, Bruno; Leggett, J. E.; Ebert, Steven C.; Craig, William A.

doi:10.1128/aac.35.7.1413

Cited by 82 publications

(48 citation statements)

References 24 publications

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“…The concept of studying the pharmacodynamics, i.e., the correlation of the effect in vivo with the pharmacokinetics, in experimental models with several different bacteria with various susceptibilities to the antibiotics in question has been attempted by several investigators (2,5,11,16,28,32,35). If different bacteria are used, the question arises as to whether the infections caused by bacteria with different virulence properties and, possibly, the different immune responses elicited by the host can provide any meaningful insight into the pharmacodynamic properties of different antibiotics with different modes of action (2,11,35).…”

Section: Discussionmentioning

confidence: 99%

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Experimental Streptococcus pneumoniae infection in mice for studying correlation of in vitro and in vivo activities of penicillin against pneumococci with various susceptibilities to penicillin

Knudsen

Frimodt‐Møller

Espersen

1995

Antimicrob Agents Chemother

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The purpose of the study was to investigate the correlation of in vitro activity with the in vivo effect and the pharmacokinetics of penicillin in the treatment of infections with pneumococci with various susceptibilities to penicillin. We used 10 pneumococcal strains for which penicillin MICs ranged from 0.016 to 8 g/ml. Time-kill curve experiments were performed with all strains. We found that the effect of penicillin in vitro is concentration independent, with a maximum effect at two to four times the MIC for penicillin-susceptible as well as penicillin-resistant pneumococci. The mouse peritonitis model with an inoculum of approximately 10 6 CFU, to which mucin was added, resulted in a reproducible lethal infection with the pneumococci. The 50% effective dose was determined for each strain, and we found a highly significant correlation between the log MIC and the log 50% effective dose of penicillin against these strains (P < 0.01). Furthermore, it was shown that the most important pharmacokinetic parameter determining the effect of penicillin in vivo was the time that the concentration of penicillin in serum was greater than the MIC.Despite the developments in antibiotics and vaccines, Streptococcus pneumoniae is still an important cause of pneumonia and meningitis (7). The increasing resistance of pneumococcal strains to penicillin in recent years and the spread of these resistant strains to many parts of the world have renewed interest in treatments for pneumococcal infections (1,6,22,27). Penicillin resistance is often followed by resistance to other antibiotics, e.g., chloramphenicol, macrolides, sulfonamides, and tetracyclines (17,22). Pneumococci are classified as fully susceptible to penicillin when the MIC is less than 0.1 g/ml, intermediately resistant when the MICs are at or between 0.1 and 1 g/ml, and highly resistant when the MIC is greater than 1 g/ml (22). In some cases of infection, higher doses of penicillin have had a sufficient effect; otherwise, other beta-lactam antibiotics such as the broad-spectrum cephalosporins and glycopeptides are recommended for use in the treatment of infections caused by these pathogens (1,6,7,17,22).We have previously shown in an experimental animal model that the most important pharmacokinetic parameter indicating an effect of beta-lactam antibiotics in vivo against penicillinsuspectible pneumococci is the time that the antibiotic concentration remains greater than the MIC (T ϾMIC ) (12, 13). Whether the same pharmacodynamic rules count for penicillin-resistant pneumococci has been the subject of only a few experimental studies, and then with only a few strains (2, 5, 16). The purpose of the present study was to investigate the correlation of in vitro activity with the in vivo effect and the pharmacokinetics of penicillin in the treatment of infections with pneumococci with various susceptibilities to penicillin. We used 10 pneumococcal strains for which penicillin MICs ranged from 0.016 to 8 g/ml in the mouse peritonitis model. MATERIALS AND METHODSBacteria, m...

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Section: Discussionmentioning

confidence: 99%

“…If different bacteria are used, the question arises as to whether the infections caused by bacteria with different virulence properties and, possibly, the different immune responses elicited by the host can provide any meaningful insight into the pharmacodynamic properties of different antibiotics with different modes of action (2,11,35).…”

Section: Discussionmentioning

confidence: 99%

Experimental Streptococcus pneumoniae infection in mice for studying correlation of in vitro and in vivo activities of penicillin against pneumococci with various susceptibilities to penicillin

Knudsen

Frimodt‐Møller

Espersen

1995

Antimicrob Agents Chemother

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“…The in vitro tests evaluated include standard and high-inoculum MIC and MBC tests, killing curve tests, incubation of MIC and MBC test cultures anaerobically as well as aerobically, and checkerboard testing for synergy when combinations of agents were used. Even in this highly controlled in vivo environment, with few variables contributed by any host immune factors and numerous in vitro test methods evaluated comparatively, it was not possible to precisely predict the in vivo outcome from quantitative MBC data (5,27,28,33,72,86,87 (26).…”

Section: Clinical Relevance Of Bactericidal Testingmentioning

confidence: 99%

Tests for bactericidal effects of antimicrobial agents: technical performance and clinical relevance

1992

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Bactericidal testing has been used for several decades as a guide for antimicrobial therapy of serious infections. Such testing is most frequently performed when bactericidal antimicrobial agent therapy is considered necessary (such as when treating infectious endocarditis or infection in an immunocompromised host). It has also been used to ensure that the infecting organism is killed by (not tolerant to) usually bactericidal compounds. However, few data are available to support the role of such tests in direct patient care. Several important variables affect the reproducibility of the test results; however, proposed reference methods are now available for performing the MBC test. With minor modifications, these can provide a standardized approach for laboratories that need to perform them. Currently, little evidence is available to support the routine use of such testing for the care of individual patients. However, testing of new (investigational) antimicrobial agents can be beneficial in determining their potential to provide bactericidal antimicrobial activity during clinical use. New methods to assess bactericidal activity are being developed, but as yet none have been rigorously tested in patient care settings; further, for most of these methods, little information is available as to which technical parameters affect their results. In clinical laboratories, all bactericidal tests must be performed with rigorously standardized techniques and adequate controls, bearing in mind the limitations of the currently available test procedures.

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“…The E max model has been successfully used to describe PK-PD relationships (12,19,21,25) in the antibacterial field. In these reports, the most frequently used efficacy parameter was the difference between the CFU in the absence and that in the presence of the antibacterial compound.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics-Pharmacodynamics of a Sordarin Derivative (GM 237354) in a Murine Model of Lethal Candidiasis

Aviles¹,

Falcoz

Román³

et al. 2000

Antimicrob Agents Chemother

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Relationships between simulated PK and PK-PD parameters and efficacy were explored. A good correlation independent of the dosing interval was observed with AUC (but not C max or t > MIC) and both AUSTC and kidney burden. Following repeated dosing every 8 h, AUC 50 (AUC at which 50% of the maximum therapeutic efficacy is obtained) was estimated as 21.7 and 37.1 g ⅐ h/ml (total concentrations) for AUSTC and kidney burden using a sigmoid E max and an inhibitory sigmoid E max PK-PD model, respectively. For an efficacy target of 90% survival, AUC was predicted as 67 g ⅐ h/ml. We conclude that the PK-PD approach is useful for evaluating relationships between PK parameters and efficacy in antifungal research. Moreover, the results obtained with this approach could be successfully applied to clinical studies.

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Correlation between in vitro and in vivo activity of antimicrobial agents against gram-negative bacilli in a murine infection model

Cited by 82 publications

References 24 publications

Experimental Streptococcus pneumoniae infection in mice for studying correlation of in vitro and in vivo activities of penicillin against pneumococci with various susceptibilities to penicillin

Experimental Streptococcus pneumoniae infection in mice for studying correlation of in vitro and in vivo activities of penicillin against pneumococci with various susceptibilities to penicillin

Tests for bactericidal effects of antimicrobial agents: technical performance and clinical relevance

Pharmacokinetics-Pharmacodynamics of a Sordarin Derivative (GM 237354) in a Murine Model of Lethal Candidiasis

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