In Vivo and in Vitro Study of Several Pharmacodynamic Effects of Meropenem

Fuentes, Fernando; Martín, María Molina; Izquierdo, Jesusa Izquierdo; Gómez-Lus, Marı́a Luisa; Prieto, J.

doi:10.3109/00365549509047048

Cited by 18 publications

(14 citation statements)

References 26 publications

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“…The numbers of CFU were counted for plotting of the killing curves. The duration of the postantibiotic effect (PAE) was calculated by the formula T Ϫ C (21,43), where T is the time required for the mean count of CFU in the lung of treated mice to increase by 1 log 10 unit above its value at the time that the antibiotic concentration in serum fell below the MIC or MBIC, and C is the time required for the mean count of CFU in the lungs of control mice to increase by 1 log unit above the viable count at time zero.…”

Section: Methodsmentioning

confidence: 99%

In Vivo Pharmacokinetics/Pharmacodynamics of Colistin and Imipenem in Pseudomonas aeruginosa Biofilm Infection

Wang

Ciofu

et al. 2012

Antimicrob Agents Chemother

176

131

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Many Pseudomonas aeruginosa isolates from the airways of patients with cystic fibrosis (CF) are sensitive to antibiotics in susceptibility testing, but eradication of the infection is difficult. The main reason is the biofilm formation in the airways of patients with CF. The pharmacokinetics (PKs) and pharmacodynamics (PDs) of antimicrobials can reliably be used to predict whether antimicrobial regimens will achieve the maximum bactericidal effect against infections. Unfortunately, however, most PK/PD studies of antimicrobials have been done on planktonic cells and very few PK/PD studies have been done on biofilms, partly due to the lack of suitable models in vivo. In the present study, a biofilm lung infection model was developed to provide an objective and quantitative evaluation of the PK/PD profile of antimicrobials. Killing curves were set up to detect the antimicrobial kinetics on planktonic and biofilm P. aeruginosa cells in vivo. Colistin showed concentration-dependent killing, while imipenem showed time-dependent killing on both planktonic and biofilm P. Although progress on biofilm research has been obtained during the past decades (48), the treatment of biofilm infections with antibiotics remains an important clinical challenge. The pharmacokinetic (PK) and pharmacodynamic (PD) profiles of an antimicrobial agent provide important information helping to establish an efficient dosing regimen (49). Therefore, PK and PD information on the activities of antimicrobial agents against biofilm-associated bacteria can contribute to better clinical treatment of biofilm-associated diseases. Unfortunately, most previous PK/PD studies of antibiotics have been done on planktonic cells, and extrapolation of the results to biofilm cells is problematic, as bacterial biofilm cells differ from cells growing in planktonic form in growth rate (36), gene expression (10, 12), and metabolism (15, 52).We have recently shown that colistin has a concentration-dependent killing and imipenem has a time-dependent killing of Pseudomonas aeruginosa biofilm cells in vitro (30). The rationale for the present study is to validate the results obtained in vitro with an in vivo model of P. aeruginosa biofilm infection in neutropenic mice.(This in vivo PK/PD study was presented in part at the 110th General Meeting of the American Society for Microbiology, San Diego, CA, May 2010 [abstr. A-2973.) MATERIALS AND METHODSStrains, chemicals, and susceptibility assay. Wild-type P. aeruginosa PAO1 (45) was used in this study. Colistin and imipenem were pharmaceutical grade. The MIC was detected by Etest (AB Biodisk, Solna, Sweden) and by a microtiter method; the minimal bactericidal concentration (MBC) for planktonic cells was detected by the microtiter method (1). The MICs and MBCs of colistin for PAO1 were 2 to 4 mg/liter and 8 mg/liter, respectively; the MICs and MBCs of imipenem were 1 mg/liter and 4 mg/liter, respectively. The minimal biofilm inhibitory concentration (MBIC) and minimal biofilm eradication concentration (MBEC) of colistin and ...

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Section: Methodsmentioning

confidence: 99%

In Vivo Pharmacokinetics/Pharmacodynamics of Colistin and Imipenem in Pseudomonas aeruginosa Biofilm Infection

Wang

Ciofu

et al. 2012

Antimicrob Agents Chemother

176

131

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“…Animal and in vitro studies conducted during the 1980s and early 1990s have particularly emphasized the consistently greater efficacy of continuous infusion or more frequent dosing of beta-lactams against Gram-negative bacteria. Although this supported the potential advantage of using continuous and prolonged infusions, the clear superiority of these methods over intermittent dosing had yet to be demonstrated (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37).…”

Section: Historical Reviewmentioning

confidence: 99%

Continuous and Prolonged Intravenous β-Lactam Dosing: Implications for the Clinical Laboratory

2016

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SUMMARYBeta-lactam antibiotics serve as a cornerstone in the management of bacterial infections because of their wide spectrum of activity and low toxicity. Since resistance rates among bacteria are continuously on the rise and the pipeline for new antibiotics does not meet this trend, an optimization of current beta-lactam treatment is needed. This review provides an overview of optimization through use of prolonged- and continuous-infusion dosing strategies compared with more traditional intermittent infusions. Included is an overview of the scientific basis for using these nontraditional prolonged- and continuous-infusion-based regimens, with a focus on major areas in which the clinical laboratory can support the clinical use of these regimens.

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“…Carbapenems show concentration-dependent killing at concentrations of up to 8 to 16 times the pathogen MIC (13) but not at high concentrations (15) and also show persistent antibiotic effects in animal and in vitro experiments (5,16,26,32). The postantibiotic effect is related to both the concentration of carbapenem employed and the duration of pathogen exposure (27).…”

Section: Discussionmentioning

confidence: 99%

“…There is a lack of inoculum effect on antibacterial activity compared to other ␤-lactams (28). The dominant pharmacodynamic index is TϾMIC for both gram-positive and gram-negative bacteria (6,15,16,20,34), as shown in in vitro and in vivo pharmacodynamic models.…”

Section: Discussionmentioning

confidence: 99%

Pharmacodynamics of the Antibacterial Effect and Emergence of Resistance to Tomopenem, Formerly RO4908463/CS-023, in an In Vitro Pharmacokinetic Model of Staphylococcus aureus Infection

MacGowan

Bowker

Noel

2008

Antimicrob Agents Chemother

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The antibacterial effects (ABE) of tomopenem (formerly RO4908463/CS-023) against seven Staphylococcus aureus strains (methicillin-resistant S. aureus [MRSA] strain tomopenem MICs, 0.5 to 16 mg/liter; methicillinsensitive S. aureus [MSSA] strain tomopenem MIC, 0.06 mg/liter) were studied in an in vitro pharmacokinetic model. Initially, two human doses were simulated, 750 mg every 8 hours (8hly) and 1,500 mg 8hly intravenously, using S. aureus at a standard inoculum of 10 6 CFU/ml. There was a rapid clearance of bacteria from the model by 12 h after drug exposure with most strains. Clearance was not related to the tomopenem MIC. The ABE of these two tomopenem dose regimens were also tested at a high inoculum, 10 8 CFU/ml; in all simulations, there was a >4-log drop in viable count at 24 h. Strains were not cleared from the model at 10 8 CFU/ml, in contrast to what was seen for the standard inoculum. When the ABE of tomopenem at 750 mg 8hly was compared to those of vancomycin, tomopenem was seen to have a superior effect, as measured by the area under the bacterial kill curve at 24 h (AUBKC 24 ) and 48 h (P < 0.05). Dose ranging studies were performed to provide time-above-MIC (T>MIC) drug exposures of 0 to 100% (8 to 10 doses per strain) with five MRSA/MSSA strains. The T>MIC for a 24-h bacteriostatic effect was 8% ؎ 5% (range, 1.3% to 15.4%); the T>MIC for a 4-log drop in viable count was 32% ؎ 18% (range, 12.8% to 36.2%). The T>MIC for a 90% maximum response using AUBKC 24 as ABE was 24.9% ؎ 15.7%. Inoculum had little impact on T>MIC exposures for ABE. There was emergence of resistance to tomopenem in the dose ranging studies, with increased growth of subpopulations on plates containing tomopenem at 2؋ and 4؋ the MIC compared to what was seen for preexposure population analysis at T>MICs of <20%. The pharmacodynamics of tomopenem against S. aureus is similar to those of other members of the carbapenem class, with the exception that MRSA is included. These data indicate that tomopenem will have clinically useful activity against MRSA at T>MICs achievable in humans.Tomopenem (formerly RO4908463/CS-023) is an injectable 2-substituted 1-␤-methyl carbapenem. It has a guanidine-pyrrolidine side chain and binds with high affinity to penicillin binding protein 1 (PBP1), PBP2, and PBP4 from Staphylococcus aureus. The MIC 50 and MIC 90 against methicillin-sensitive S. aureus (MSSA) are 0.12 and 0.12 to 0.25 mg/liter (17,19,32). For methicillin-resistant S. aureus (MRSA), the MIC 50 and MIC 90 are 2 and 4 to 16 mg/liter (17,19,32). This contrasts to imipenem and meropenem, which have MRSA MIC 90 values of 32 and 16 to 32 mg/liter. Tomopenem retains in vitro potency against extended-spectrum ␤-lactamase-producing Escherichia coli and Klebsiella spp. as well as Pseudomonas aeruginosa (8,17,19,33).The pharmacokinetics studies with male healthy volunteers indicate relatively typical carbapenem pharmacokinetics except for a prolonged serum half-life of about 2 h, which is related to a lack of renal tubular secretion (29). Tomop...

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In Vivo and in Vitro Study of Several Pharmacodynamic Effects of Meropenem

Cited by 18 publications

References 26 publications

In Vivo Pharmacokinetics/Pharmacodynamics of Colistin and Imipenem in Pseudomonas aeruginosa Biofilm Infection

In Vivo Pharmacokinetics/Pharmacodynamics of Colistin and Imipenem in Pseudomonas aeruginosa Biofilm Infection

Continuous and Prolonged Intravenous β-Lactam Dosing: Implications for the Clinical Laboratory

Pharmacodynamics of the Antibacterial Effect and Emergence of Resistance to Tomopenem, Formerly RO4908463/CS-023, in an In Vitro Pharmacokinetic Model of Staphylococcus aureus Infection

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