Evaluation of the post-antibiotic effect in vivo for the combination of a ß-lactam antibiotic and a ß-lactamase inhibitor: ceftazidime-avibactam in neutropenic mouse thigh and lung infections.

The post-antibiotic effect (PAE) of ceftazidime-avibactam in vivo was evaluated using models of thigh- and lung-infection with Pseudomonas aeruginosa in neutropenic mice. In thigh-infected mice, the PAE was negative (-2.18 to -0.11 h) for three of four strains: caused by a 'burst' of rapid bacterial growth after the drug concentrations had fallen below their pre-specified target values. With lung infection, PAE was positive, and longer for target drug concentrations in ELF (>2 h) than plasma (1.69-1.88 h). The time to the start of regrowth was quantified as a new parameter, PAER, which was positive (0.35-1.00 h) in both thigh- and lung-infected mice. In the context that measurements of the PAE of ß-lactam/ß-lactamase inhibitor combinations in vivo have not previously been reported, it is noted that the negative values were consistent with previous measurements of the PAE of ceftazidime-avibactam in vitro and of ceftazidime alone in vivo.

Pharmacodynamics of nitrofurantoin at different pH levels against pathogens involved in urinary tract infections.

BACKGROUND: Urinary tract infections are among the most common human infections. Due to the progressive increase in ESBL-producing bacteria and the unavailability of new antibiotics, re-evaluation of 'old' antibiotics is needed. However, the pharmacodynamics of nitrofurantoin under variable pH conditions are poorly understood. We determined the pharmacodynamic properties of nitrofurantoin at different pH levels using time-kill assays. METHODS: Time-kill assays were performed at four pH levels (5.5, 6.5, 7.5 and 8.5), exposing the bacteria to 2-fold increasing concentrations from 0.125 to 32 times the MIC. Seven ESBL-positive and two ESBL-negative strains (MICs 8-32 mg/L) were used. The Δlog10 cfu/mL values at 6 and 24 h were plotted against each log10-transformed concentration and analysed with non-linear regression analysis using the sigmoid maximum effect model with variable slope. Geometric means normalized by the MIC of the EC50, stasis and 1 and 3 log10 cfu/mL kill were calculated. RESULTS: Minimum bactericidal effects differed significantly by species and pH level. At pH 5.5-6.5 bactericidal effects were observed at ≥ 0.5 × MIC for Escherichia coli and Enterobacter cloacae. At pH 8.5 only the two highest concentrations were considered bactericidal. Strong pH-dependent pharmacodynamic output parameters were observed in 6 h and especially 24 h modelling. At 24 h, pH 5.5-6.5 for E. coli and Klebsiella pneumoniae required significantly lower nitrofurantoin concentrations compared with pH 7.5 or 8.5. Although for E. cloacae similar strong decreasing trends were visible with decreasing pH, none of the tested pharmacodynamic parameters was significant. CONCLUSIONS: Nitrofurantoin bactericidal activity against Enterobacteriaceae significantly increases at lower pH levels. Bactericidal activity of nitrofurantoin may be overestimated or underestimated, which may have implications for therapy and the interpretation of clinical breakpoints.

Pharmacodynamics of Ceftazidime and Avibactam in Neutropenic Mice with Thigh or Lung Infection.

Avibactam is a new non-ß-lactam ß-lactamase inhibitor that shows promising restoration of ceftazidime activity against microorganisms producing Ambler class A extended-spectrum ß-lactamases (ESBLs) and carbapenemases such as KPCs, class C ß-lactamases (AmpC), and some class D enzymes. To determine optimal dosing combinations of ceftazidime-avibactam for treating infections with ceftazidime-resistant Pseudomonas aeruginosa, pharmacodynamic responses were explored in murine neutropenic thigh and lung infection models. Exposure-response relationships for ceftazidime monotherapy were determined first. Subsequently, the efficacy of adding avibactam every 2 h (q2h) or q8h to a fixed q2h dose of ceftazidime was determined in lung infection for two strains. Dosing avibactam q2h was significantly more efficacious, reducing the avibactam daily dose for static effect by factors of 2.7 and 10.1, whereas the mean percentage of the dosing interval that free drug concentrations remain above the threshold concentration of 1 mg/liter (%fT>C(T) 1 mg/liter) yielding bacteriostasis was similar for both regimens, with mean values of 21.6 (q2h) and 18.5 (q8h). Dose fractionation studies of avibactam in both the thigh and lung models indicated that the effect of avibactam correlated well with %fT>C(T) 1 mg/liter. This parameter of avibactam was further explored for four P. aeruginosa strains in the lung model and six in the thigh model. Parameter estimates of %fT>C(T) 1 mg/liter for avibactam ranged from 0 to 21.4% in the lung model and from 14.1 to 62.5% in the thigh model to achieve stasis. In conclusion, addition of avibactam enhanced the effect of ceftazidime, which was more pronounced at frequent dosing and well related with %fT>C(T) 1 mg/liter. The thigh model appeared more stringent, with higher values, ranging up to 62.5% fT>C(T) 1 mg/liter, required for a static effect.

Pharmacokinetics and penetration of ceftazidime and avibactam into epithelial lining fluid in thigh- and lung-infected mice.

Ceftazidime and the ß-lactamase inhibitor avibactam constitute a new, potentially highly active combination in the battle against extended-spectrum-ß-lactamase (ESBL)-producing bacteria. To determine possible clinical use, it is important to know the pharmacokinetic profiles of the compounds related to each other in plasma and the different compartments of infection in experimentally infected animals and in humans. We used a neutropenic murine thigh infection model and lung infection model to study pharmacokinetics in plasma and epithelial lining fluid (ELF). Mice were infected with ca. 10(6) CFU of Pseudomonas aeruginosa intramuscularly into the thigh or intranasally to cause pneumonia and were given 8 different (single) subcutaneous doses of ceftazidime and avibactam in various combined concentrations, ranging from 1 to 128 mg/kg of body weight in 2-fold increases. Concomitant samples of serum and bronchoalveolar lavage fluid were taken at up to 12 time points until 6 h after administration. Pharmacokinetics of both compounds were linear and dose proportional in plasma and ELF and were independent of the infection type, with estimated half-lives (standard deviations [SD]) in plasma of ceftazidime of 0.28 (0.02) h and of avibactam of 0.24 (0.04) h and volumes of distribution of 0.80 (0.14) and 1.18 (0.34) liters/kg. The ELF-plasma (area under the concentration-time curve [AUC]) ratios (standard errors [SE]) were 0.24 (0.03) for total ceftazidime and 0.27 (0.03) for unbound ceftazidime; for avibactam, the ratios were 0.20 (0.02) and 0.22 (0.02), respectively. No pharmacokinetic interaction between ceftazidime and avibactam was observed. Ceftazidime and avibactam showed linear plasma pharmacokinetics that were independent of the dose combinations used or the infection site in mice. Assuming pharmacokinetic similarity in humans, this indicates that similar dose ratios of ceftazidime and avibactam could be used for different types and sites of infection.