Assessment and modelling of antibacterial combination regimens.

BACKGROUND: The increasing global prevalence of multidrug-resistant bacteria is forcing clinicians to prescribe combination antibiotic regimens to treat serious infections. Currently, the joint activity of a combination is quantified by comparing the observed and expected effects using a reference model. These reference models make different assumptions and interpretations of synergy. They fail to: (i) account for multiple bacterial subpopulations with differing susceptibilities; (ii) quantify or interpret the explicit interaction (synergy/antagonism) mechanisms; and (iii) accommodate spontaneous mutations. AIMS: To develop better study designs, mathematical models, metrics and pharmacodynamic analyses to assist with the identification of highly active combinations that are translatable to the clinical context to address the mounting antibiotic resistance threat. SOURCES: PubMed, references of identified studies and reviews, and personal experience when evidence was lacking. CONTENT: We reviewed metrics and approaches for quantifying the joint activity of the combination. The first example is using experimental data from an in vitro checkerboard synergy panel to develop and illustrate a less model-dependent method for assessing combination regimens. In the second example a pharmacokinetic/pharmacodynamic model was developed using mechanism-based mathematical modelling and monotherapy and combination therapy data obtained from an in vitro hollow fibre infection model evaluating linezolid and rifampin regimens against Mycobacterium tuberculosis. IMPLICATIONS: Mechanism-based mathematical approach provides an excellent platform for describing the time course of effect while taking into account the mechanisms of different antibiotics and differing pathogen susceptibilities. This approach allows for the future integration of 'omics' data describing host-pathogen interactions, that will provide a systems-level understanding of the underlying infectious process, and enable the design of effective combination therapies.

Enterococcal bacteraemia: factors influencing mortality, length of stay and costs of hospitalization.

Enterococci are a major cause of nosocomial bacteraemia. The impacts of vanB vancomycin resistance and antibiotic therapy on outcomes in enterococcal bacteraemia are unclear. Factors that affect length of stay (LOS) and costs of managing patients with enterococcal bacteraemia are also unknown. This study aimed to identify factors associated with mortality, LOS and hospitalization costs in patients with enterococcal bacteraemia and the impact of vancomycin resistance and antibiotic therapy on these outcomes. Data from 116 patients with vancomycin-resistant Enterococci (VRE), matched 1:1 with patients with vancomycin-susceptible Enterococcus (VSE), from two Australian hospitals were reviewed for clinical and economic outcomes. Univariable and multivariable logistic and quantile regression analyses identified factors associated with mortality, LOS and costs. Intensive care unit admission (OR, 8.57; 95% CI, 3.99-18.38), a higher burden of co-morbidities (OR, 4.55; 95% CI, 1.83-11.33) and longer time to appropriate antibiotics (OR, 1.02; 95% CI, 1.01-1.03) were significantly associated with mortality in enterococcal bacteraemia. VanB vancomycin resistance increased LOS (4.89 days; 95% CI, 0.56-11.52) and hospitalization costs (AU$ 28 872; 95% CI, 734-70 667), after adjustment for confounders. Notably, linezolid definitive therapy was associated with lower mortality (OR, 0.13; 95% CI, 0.03-0.58) in vanB VRE bacteraemia patients. In patients with VSE bacteraemia, time to appropriate antibiotics independently influenced mortality, LOS and hospitalization costs, and underlying co-morbidities were associated with mortality. The study findings highlight the importance of preventing VRE bacteraemia and the significance of time to appropriate antibiotics in the management of enterococcal bacteraemia.

An in vivo assessment of the tobramycin/ticarcillin interaction in cystic fibrosis patients.

A non-blinded, randomized, cross-over investigation of the pharmacokinetic interaction between tobramycin and ticarcillin was performed in 18 healthy cystic fibrosis (CF) patients with normal renal function. On consecutive mornings the patients were given either tobramycin intravenously (i.v.) over 3-5 min (TOB phase), or tobramycin i.v. over 3-5 min followed immediately by ticarcillin infused i.v. over 20-30 min (TOB+TIC phase). Capillary blood samples were taken 30 min and 330 min after administration of the tobramycin dose in each phase. Tobramycin was measured in serum by fluorescence polarization immunoassay (TDx). There were decreases in serum tobramycin concentrations of 11% at 30 min (P < 0.001) and 330 min (P = 0.012) when measured in the presence of ticarcillin. No difference in elimination half-life was found (TOB phase 95 +/- 13 min, TOB+TIC phase 95 +/- 13 min, P = 0.86). The volume of distribution and clearance of tobramycin increased by 14% (P < 0.001) and 13% (P < 0.001), respectively, in the presence of ticarcillin. This interaction appears to be of minor clinical importance but pharmacokinetic studies of tobramycin should exclude concurrent use of ticarcillin.