Clinical review: Balancing the therapeutic, safety, and economic issues underlying effective antipseudomonal carbapenem use

Abstract

Antipseudomonal carbapenems have played a useful role in our antimicrobial armamentarium for 20 years. However, a review of their use during that period creates concern that their clinical effectiveness is critically dependent on attainment of an appropriate dosing range. Unfortunately, adequate carbapenem dosing is missed for many reasons, including benefit/risk misconceptions, a narrow therapeutic window for imipenem and meropenem (due to an increased rate of seizures at higher doses), increasingly resistant pathogens requiring higher doses than are typically given, and cost containment issues that may limit their use. To improve the use of carbapenems, several initiatives should be considered: increase awareness about appropriate treatment with carbapenems across hospital departments; determine optimal dosing regimens for settings where multidrug resistant organisms are more likely encountered; use of, or combination with, an alternative antimicrobial agent having more favorable pharmacokinetic, pharmacodynamic, or adverse event profile; and administer a newer carbapenem with lower propensity for resistance development (for example, reduced expression of efflux pumps or greater stability against carbapenemases).

Carbapenem antibiotics for serious infections

“…25 Ertapenem has a reported overall seizure rate of 0.5%, 25 and doripenem seems to lack proconvulsive activity. 26 Cephalosporins and quinolones are strongly associated with Clostridium difficile infection. Carbapenems have been implicated too, 27 but analysis is complicated because many patients receiving these drugs have already received multiple other antibiotics.…”

Pharmacodynamic profiling of doripenem, imipenem and meropenem against prevalent Gram-negative organisms in the Asia-Pacific region

“…In response to these challenging trends in resistance, carbapenems are increasingly being utilised as a therapeutic option both for empirical and direct therapy against frequently isolated pathogens such as Pseudomonas aeruginosa, Acinetobacter spp. and extended-spectrum ␤-lactamase-producing Enterobacteriaceae [4][5][6][7].…”

Pharmacokinetics of meropenem in septic patients on sustained low-efficiency dialysis: a population pharmacokinetic study

“…When applying high doses of meropenem to ensure bactericidal activity as suggested by our simulations, clinicians need to balance this benefit against potential side effects such as seizures. However, the incidence of meropenem-associated seizures is described as low (<1%) and they are usually reversible on discontinuation and manageable with anticonvulsants [ 52 ].…”