Bactericidal activity, post antibiotic effect and modified controlled effective regrowth time of meropenem at high concentrations

Ke, Bowker; Ha, Holt; Ds, Reeves; Ap, MacGowan

doi:10.1093/jac/38.6.1055

Cited by 23 publications

(6 citation statements)

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“…β‐Lactams are time‐dependent antibiotics and their activity is associated with f T > MIC . In line with their PK/PD index, prolonged infusions, such as extended infusions (EI; infusions for ~ 50% of a dosing interval) or continuous infusions (CI) have been explored as strategies to optimize β‐lactam activity.…”

Section: Pharmacokinetics and Pharmacodynamics Of β‐Lactamsmentioning

confidence: 99%

β‐Lactam pharmacokinetics and pharmacodynamics in critically ill patients and strategies for dose optimization: A structured review

Sinnollareddy

Roberts

Lipman

et al. 2012

Clin Exp Pharma Physio

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SUMMARY1. Infections and related sepsis are two of the most prevalent issues in the care of critically ill patients, with mortality as high as 70%. Appropriate antibiotic selection, as well as adequate dosing, is important to improve the clinical outcome for these patients.2. b-Lactams are the most common antibiotic class used in critically ill sepsis patients because of their broad spectrum of activity and high tolerability. b-Lactams exhibit time-dependent antibacterial activity. Therefore, concentrations need to be maintained above the minimum inhibitory concentration (MIC) of pathogenic bacteria. b-Lactams are hydrophilic antibiotics with small distribution volumes similar to extracellular water and are predominantly excreted through the renal system.3. Critically ill patients experience a myriad of physiological changes that result in changes in the pharmacokinetics (PK) of hydrophilic drugs such as b-lactams. A different approach to dosing with b-lactams may increase the likelihood of positive outcomes considering the pharmacodynamics (PD) of b-lactams, as well as the changes in PK in critically ill patients.4. The present review describes the strategies for dose optimization of b-lactams in critically ill patients in line with the PK and PD of these drugs.

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Section: Pharmacokinetics and Pharmacodynamics Of β‐Lactamsmentioning

confidence: 99%

β‐Lactam pharmacokinetics and pharmacodynamics in critically ill patients and strategies for dose optimization: A structured review

Sinnollareddy

Roberts

Lipman

et al. 2012

Clin Exp Pharma Physio

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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%

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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“…The figure shows that concentrations higher than 4 mg/L or four times the MIC-the MIC of this strain was 1 mg/L-do not result in increased killing activity. Bacterial killing at concentrations greater than 4-5 times the MIC does not increase with Enterobacteriaceae, Staphylococcus aureus or Pseudomonas aeruginosa (Hyatt et al 1995;Bowker et al 1996;Mouton and Vinks 2005b). Slight differences in degree and rate of killing may exist between penicillins, cephalosporins and carbapenems, with carbapenems being most rapidly bactericidal and penicillins least against Gramnegative pathogens (Periti and Nicoletti 1999).…”

Section: In Vitro Pharmacodynamic Effectsmentioning

confidence: 99%

Continuous Infusion of Beta-lactam Antibiotics

Muller

Mouton

2013

Fundamentals of Antimicrobial Pharmacokinetics and Pharmacodynamics

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For beta-lactam antibiotics continuous infusion can be used to optimise antibiotic therapy. Pre-clinical studies in rodents and in vitro studies have shown the benefits of continuous infusion when compared to intermittent dosing. Pharmacokinetic studies in humans have shown an improved probability of target attainment for continuous infusion. However, the relationship between continuous infusion and improved clinical outcome is ambiguous. The superiority of continuous infusion over intermittent dosing in clinical outcome studies is most often documented in special subgroups, such as critically ill patients or patients infected with less-susceptible micro-organisms. Methods to calculate doses during continuous infusion and practical issues, such as stability of antimicrobial solutions, are described.

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Bactericidal activity, post antibiotic effect and modified controlled effective regrowth time of meropenem at high concentrations

Cited by 23 publications

References 0 publications

β‐Lactam pharmacokinetics and pharmacodynamics in critically ill patients and strategies for dose optimization: A structured review

β‐Lactam pharmacokinetics and pharmacodynamics in critically ill patients and strategies for dose optimization: A structured review

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

Continuous Infusion of Beta-lactam Antibiotics

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