, 2000) and this has an impact on the PK/PD

parameters of biofilm killing. The PK/PD parameter for the beta-lactam killing of biofilms formed by P. aeruginosa expressing low basal levels of beta-lactamase is, as for planktonically grown cells, the time above MIC but higher concentrations of antibiotics and longer periods of action are required to eliminate biofilm compared with planktonically grown cells (Hengzhuang et al., 2011, 2012). Continuous administration of ceftazidime would thus be better for biofilm treatment, which in this way will be exposed for longer to concentrations above the MIC (T > MIC). Compared with intermittent infusion, continuous infusion at normal daily doses is more likely to achieve optimal T > MIC PD goals for intermediate and borderline resistant organisms with selleck products an MIC of ceftazidime up to 16 mg L−1 (Prescott

et al., 2011). Although the results of studies comparing the efficacy and safety of continuous-infusion and intermittent-infusion antipseudomonal Pexidartinib order beta-lactam therapy are promising, there is insufficient evidence to recommend continuous infusion for routine use. However, continuous-infusion dosing with ceftazidime does appear to be a reasonable option for patients who have not responded to traditional dosing methods or who have multidrug-resistant P. aeruginosa isolates. In the case of biofilms formed by P. aeruginosa expressing high basal levels of beta-lactamase,

a concentration-dependent killing of the biofilm was observed, supporting the idea of impaired penetration of beta-lactam antibiotics in the biofilm due to inactivation of the beta-lactam molecules by hydrolysing enzymes (our unpublished data). A similar effect was observed in biofilms of nfxB mutants of P. aeruginosa which show an increased Fludarabine datasheet extracellular level of AmpC beta-lactamase that impaired biofilm killing (Mulet et al., 2011). Treatment with beta-lactamase-stable compounds such as meropenem or combinations with beta-lactamase inhibitors might improve penetration of the drug into the biofilm and ensure a better effect of treatment with beta-lactams. This effect was observed in vitro during treatment of biofilm-grown P. aeruginosa with combination ceftazidime and aztreonam (Hoiby et al., 2010), probably because aztreonam acts as a beta-lactamase inhibitor (Giwercman et al., 1992), and with meropenem (Moskowitz et al., 2004; Hill et al., 2005). Efflux pumps MexAB-OprM, MexCD-OprJ, MexEF-OprN and MexXY, which play an important role in the resistance to antibiotics of planktonic P. aeruginosa, have been considered to have no impact on biofilm tolerance (De Kievit et al., 2001). However, recent studies are starting to modify this perception, as it has been suggested that MexAB-OprM and MexCD-oprJ are involved in biofilm tolerance to the macrolide azithromycin (Gillis et al.