Optimising utility of the carbapenem class
Abstract number: 1732_184
Increasing antibiotic resistance and a lack of new drug classes in development are driving the need to optimise use of currently available drugs. The goal of antimicrobial chemotherapy is to optimise the combined pharmacokinetic (PK) and pharmacodynamic (PD) profile of a drug so that the greatest percentage of patients achieves the PD target associated with a favourable outcome, while minimising the development of resistant organisms. Integration of population PK, a PD target, and microbiologic surveillance data by Monte Carlo simulations can generate an empirical dosing strategy that maximises the likelihood that an antibiotic regimen achieves the desired PD end point (exposure target). For b-lactams, the exposure target is the percentage of time that free drug levels are above the minimum inhibitory concentration (T > MIC). For carbapenems, the T > MIC requirement is lower than for other b-lactams.
By extending the infusion period to achieve the necessary T > MIC, a lower dose can achieve the same efficacy as a higher dose, while lowering cost and potential toxicity. For example, a recent publication showed that a 1-g 0.5-h infusion of meropenem has a 77.1% rate of target attainment against Pseudomonas aeruginosa isolated from hospitals in Hungary, whereas a 3-h infusion of 0.5 g meropenem would have an 83.8% rate of target attainment. In a retrospective study that compared 0.5 h piperacillin/tazobactam infusions (3.375 g, q6h) with 4-h infusions (3.375 g, q8h) in patients infected with P. aeruginosa, the 4-h infusions reduced 14-day mortality from 31.6% to 12.2% (P = 0.02) and median length of stay from 38 to 21 days in patients with APACHE II scores ≥17 (P = 0.02).
Doripenem is more stable upon reconstitution than other carbapenems, potentially making it more convenient and easier to use as an extended infusion. Furthermore, the study design for the doripenem ventilator-associated pneumonia phase 3 trial includes an extended infusion regimen (0.5 g over 4 h).
In conclusion, the same dose of an antibiotic has the capacity to increase efficacy for more resistant infections if infused over an extended period. Extended infusion of a lower dose of antibiotic may produce efficacy equivalent to shorter, higher-dose infusions while reducing both toxicity and the emergence of resistance. Extended infusion of a carbapenem, such as doripenem, that has neither seizure potential nor high resistance selection is a particularly promising strategy for serious infections.
|Session name:||European Society of Clinical Microbiology and Infectious Diseases|
|Location:||ICC, Munich, Germany|
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