Bactericidal activity of meropenem against Pseudomonas aeruginosa

Yourassowsky, E; Linden, M. P. Van der; Lismont, M.J.; Crokaert, Françoise; Glupczynski, Youri

doi:10.1093/jac/24.suppl_a.169

Cited by 9 publications

(6 citation statements)

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“…␤-Lactams are not considered to display concentration-dependent activity; however, this usually refers to activity at concentrations above the MIC. This study verifies the findings of others which demonstrated concentration-dependent activity of imipenem and meropenem over a range of concentrations (5,21). For both drugs, concentrations of Ն4 times the MIC resulted in killing of 3 log units that was maintained for 24 h. In contrast, Flukiger et al (6) observed no concentrationdependent killing by imipenem of P. aeruginosa when comparing concentrations of 2 and 10 times the MIC.…”

Section: Discussionsupporting

confidence: 90%

“…These concentration-dependent effects on regrowth were verified by the spectrophotometric analysis. Other investigators have demonstrated effects of carbapenems at concentrations below the MIC (15,21). Our findings were similar, with demonstrable concentration-dependent activity at concentration/MIC ratios of as low as 0.25 times the MIC for both agents.…”

Section: Discussionsupporting

confidence: 89%

“…These differences in affinity for PBPs may explain the differences in the relative potencies of these agents and may affect their pharmacodynamic profiles. Other time-kill studies of imipenem and meropenem with P. aeruginosa have demonstrated concentration-dependent killing over a range of 0.5 to 8 times the MIC (5,21). However, the number of sampling points and range of concentrations studied precluded an accurate assessment of the AUKC or early killing rates as well as the determination of the absolute minimal and maximal effects of these agents.…”

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confidence: 99%

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Comparative in vitro pharmacodynamics of imipenem and meropenem against Pseudomonas aeruginosa

White

Friedrich

Burgess

et al. 1996

Antimicrob Agents Chemother

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MICs are commonly used to assess the in vitro activities of antimicrobial agents; however, they provide minimal information on the pattern of bacterial activities. Time-kill studies with extensive sampling allow assessment of both the rate and extent of bacterial killing and regrowth. We compared imipenem and meropenem by both MIC-MBC testing and a time-kill study with P. aeruginosa 27853. In the time-kill study, concentration/MIC ratios ranging from 0.0625 to 32 times the MIC were studied. The kill rate, time to 99.9% kill, doubling time of regrowth, and area under the bacterial killing curve (AUKC) were evaluated. Degradation during the testing procedure was accounted for by assessing actual drug exposure as determined by the area under the concentration-time curve. Pharmacodynamic parameters were compared by using the Wilcoxon signed-rank test. The modal MIC and MBC for imipenem were 2 and 4 micrograms/ml, respectively, and those for meropenem were 0.25 and 0.5 microgram/ml, respectively. In the time-kill study, both agents displayed concentration-dependent activity over a range of 0.25 to 4 times the MIC. Initial killing (0 to 1 h) was faster with imipenem at the same concentration/MIC ratios (P = 0.0506). The time to 99.9% kill was approximately 5 h for both agents. When regrowth occurred, the doubling rate for imipenem, which was the same as that for the growth control, was twice as rapid as that for meropenem. At the same concentrations, the AUKCs over 24 h were lower for meropenem than for imipenem (P = 0.0280); however, when normalized by MIC, imipenem resulted in smaller AUKCs. Comparison of plots of area under the concentration-time curve versus AUKC, which accounted for drug degradation and actual drug exposure, revealed that meropenem was three times more active than imipenem, rather than the eightfold difference suggested by MICs. Time-kill curves with extensive sampling and measurement of actual drug exposure, rather than traditional MIC testing, may more accurately assess differences in the in vitro activities of antimicrobial agents.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 99%

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Comparative in vitro pharmacodynamics of imipenem and meropenem against Pseudomonas aeruginosa

White

Friedrich

Burgess

et al. 1996

Antimicrob Agents Chemother

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“…This phenomenon suggests that meropenem has different target-binding affinities and/or route or access through the outer membrane of this bacterial species [7]. For Pseudomonas aeruginosa we have previ ously showed also a lag of 2 h in killing for meropenem [11].…”

Section: Discussionmentioning

confidence: 91%

Antibacterial Effects of Meropenem and Imipenem against <i>Haemophilus influenzae</i>

Yourassowsky¹,

Linden²,

Crokaert³

1991

Chemotherapy

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Phase contrast microscopy, killing curves and turbidimetric growth curves were used in a comparative study of the antibacterial effects of imipenem and meropenem on Haemophilus influenzae. The minimal inhibitory concentrations (MICs) and their ranges of meropenem and imipenem using five β-lactamase-producing strains of H. influenzae were 0.03 (0.015–0.06) and 0.6 (0.5–1) μg/ml, respectively. Imipenem and meropenem induced spheroplast formation in cultures. Killing curves showed a bacteriostatic activity for meropenem and imipenem for MIC values, and a lag of 2 h in killing for MIC × 2 to MIC × 64. For these concentrations the killing rates of the two antibiotics were similar. Turbidimetric growth curves showed a higher early increase in optical density for meropenem. As far as the MIC value of meropenem was 10 times lower than the MIC value of imipenem, we may conclude that meropenem was more active than imipenem on β-lactamase-producing strains of H. influenzae.

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“…Several attempts have been made to compensate for this effect. (i) The antimicrobial activity of constant concentrations of antibiotics may be examined in a static system in which the bacterial culture is not diluted during the investigation (12). (ii) Dynamic in vitro models which do not allow bacteria to be washed out have been developed (1,2).…”

mentioning

confidence: 99%

Mathematical corrections for bacterial loss in pharmacodynamic in vitro dilution models

Keil

Wiedemann

1995

Antimicrob Agents Chemother

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In vitro dilution models are used to simulate in vivo drug concentration-time profiles and thus to study the effects of various antibiotic concentrations on the bacteria investigated. The major disadvantage of these models is permanent dilution of the bacterial culture, which falsifies the resulting kill curves. Known equations, which usually correct bacterial loss by simple first-order kinetics, do not take into account special test conditions, such as variable elimination rate constants, exceptionally long periods of investigation, or formation of biofilms. In the present investigation, we examined the validity of these equations with regard to the test conditions mentioned. We simulated the concentration-time curves resulting from continuous infusion of 1,000 mg of meropenem with steady-state levels of 2.5, 5.0, and 7.5 g/ml in an in vitro dilution model. The resulting kill curves were compared with the kill curves obtained from incubation of bacteria in an undiluted system with meropenem at constant concentrations corresponding to the above-mentioned steady-state levels. Comparison of the matching kill curves showed that the common corrections, which do not consider the formation of biofilms in the compartments, partly overestimated the effect of bacterial dilution. We defined a factor, f, as an extension to the known equations which compensates for the effect of biofilms. Another extension was developed to allow the investigation of variable elimination rate constants. With the help of these extended mathematical corrections, we were able to fit the kill curves resulting from the in vitro dilution model exactly to the kill curves given by an undiluted system. Several in vitro kinetic models which simulate in vivo drug concentration-time profiles use continuous dilution to fit drug concentrations to the corresponding serum pharmacokinetics (4). The major disadvantage of these models is inevitable dilution of the bacterial culture, which falsifies the resulting kill curves. Several attempts have been made to compensate for this effect. (i) The antimicrobial activity of constant concentrations of antibiotics may be examined in a static system in which the bacterial culture is not diluted during the investigation (12). (ii) Dynamic in vitro models which do not allow bacteria to be washed out have been developed (1, 2). (iii) The loss of bacteria in an in vitro dilution model may be compensated for by mathematical correction.In the present report, we have summarized the previously existing equations (5,8,11) and investigated their validity with regard to different test conditions by simulating continuous infusion of meropenem with steady-state levels of 2.5, 5.0, and 7.5 g/ml in an in vitro dilution model. The resulting time-kill curves were compared with the kill curves resulting from incubation of test bacteria with meropenem at constant concentrations of 2.5 to 7.5 g/ml in a static system (batch culture). We assumed that bacterial growth in the batch culture is not limited by the supply of nutrients as long a...

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Bactericidal activity of meropenem against Pseudomonas aeruginosa

Cited by 9 publications

References 0 publications

Comparative in vitro pharmacodynamics of imipenem and meropenem against Pseudomonas aeruginosa

Comparative in vitro pharmacodynamics of imipenem and meropenem against Pseudomonas aeruginosa

Antibacterial Effects of Meropenem and Imipenem against <i>Haemophilus influenzae</i>

Mathematical corrections for bacterial loss in pharmacodynamic in vitro dilution models

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