Pharmacokinetics-pharmacodynamics of tazobactam in combination with cefepime in an in vitro infection model

We previously demonstrated that for tazobactam administered in combination with ceftolozane, the pharmacokinetic-pharmacodynamic (PK-PD) index that best described tazobactam efficacy was the percentage of the dosing interval that tazobactam concentrations were above a threshold (%T>threshold). Using data from studies of Enterobacteriaceae-producing ESBL, a relationship between tazobactam %T>threshold and reduction in log10 CFU from baseline, for which tazobactam threshold concentration was the product of the isolate's ceftolozane-tazobactam MIC value and 0.5, was identified. However, since the kinetics of cephalosporin hydrolysis vary among ESBLs and compounds, it is likely that the translational relationship to derive the tazobactam threshold concentration varies among enzymes and compounds. Using a one-compartment in vitro infection model, the PK-PD of tazobactam administered in combination with cefepime was characterized and a translational relationship across ESBL-producing Enterobacteriaceae was developed. Four clinical isolates, two Escherichia coli and two Klebsiella pneumoniae, known to produce CTX-M-15 β-lactamase enzymes and displaying cefepime MIC values of 2 to 4 mg/L in the presence of 4 mg/L tazobactam, were evaluated. Tazobactam threshold concentrations from 0.0625-1 times the tazobactam-potentiated cefepime MIC value were considered. The threshold that best described the relationship between tazobactam %T>threshold and change in log10 CFU from baseline was the product of 0.125 and the cefepime-tazobactam MIC (R2=0.813). The magnitude of %T>threshold associated with net bacterial stasis and a 1-log10 CFU/mL reduction from baseline at 24 hours was 21.9 and 52.8%, respectively. These data will be useful to support the identification of tazobactam dosing regimens in combination with cefepime for evaluation in future clinical studies

Dose Range Evaluation of Mycograb C28Y Variant (MYC123 C28Y), a Human Recombinant Antibody Fragment to Heat Shock Protein 90, In Combination with Amphotericin B-Desoxycholate for the Treatment of Murine Systemic Candidiasis

Systemic candidiasis causes significant mortality in patients despite amphotericin B (AMB) therapy. Mycograb C28Y variant, a human recombinant antibody fragment to heat shock protein-90, is closely related to Mycograb, which showed a survival advantage in combination with AMB in a phase 3 human trial. The Mycograb C28Y variant could potentially increase the antifungal effect of AMB. Method: The interaction between AMB-desoxycholate (DAMB) and the Mycograb C28Y variant was characterized in vitro by a checkerboard method. Quantitative cultures of kidneys, livers, and spleens of neutropenic mice with systemic Candida albicans infections were used to assess the in vivo interaction between 1.4 mg/kg/d of DAMB and 0.15, 1.5, and 15 mg/kg/d of the Mycograb C28Y variant after 1, 3, and 5 days of therapy. DAMB and Mycograb C28Y variant monotherapies, vehicle, and a no-treatment arm served as controls. Also, single- and multi-dose pharmacokinetics for the Mycograb C28Y variant were determined. Results: Indifference or synergy between DAMB and the Mycograb C28Y variant was seen in two trials by the checkerboard method. The pharmacokinetics of the Mycograb C28Y variant was best described by a 2-compartment model with a median serum t1/2α of ~0.198 h and a t1/2β of ~1.77 h. In mice, DAMB together with the Mycograb C28Y variant was no more effective than AMB alone (p > 0.05 by ANOVA). The Mycograb C28Y variant alone had no antifungal activity. Conclusion: The Mycograb C28Y variant in combination with DAMB offered no benefit over DAMB monotherapy in a neutropenic murine model of systemic candidiasis

Pharmacokinetic/pharmacodynamic considerations for new and current therapeutic drugs for uncomplicated gonorrhoea—challenges and opportunities

BACKGROUND: Increasing multidrug resistance rates in Neisseria gonorrhoeae have raised concerns and an urgent call for new antibiotics for treatment of gonorrhoea. Several decades of subdued drug development in this field and the recent failures of two new antibiotics to show non-inferiority compared with the current first-line antibiotics ceftriaxone plus azithromycin highlight the need for improved preclinical tools to predict clinical outcome of new drugs in the development process. OBJECTIVES: To summarize current pharmacokinetic/pharmacodynamic (PK/PD) knowledge and dose-finding strategies for antibiotics against gonorrhoea. SOURCES: Literature review of published papers and discussions by global experts at a special workshop on this topic. CONTENT: We review current knowledge of gonococcal specific PK/PD principles and provide an update on new in vitro and in vivo models to correlate drug exposure with clinical outcome, and identify challenges and gaps in gonococcal therapeutic research. IMPLICATIONS: Identifying the ideal antimicrobial agent and dose for treating uncomplicated urogenital and pharyngeal gonococcal disease requires appropriate validated non-clinical PK/PD models. Recent advances in adapting in vitro and in vivo models for use in gonorrhoea are an important step for enabling the development of new drugs with reduced risk of failure in Phase 3 clinical development and diminish the risk of emergence of resistance

The Use of Streptolysin O for the Treatment of Scars, Adhesions and Fibrosis: Initial Investigations Using Murine Models of Scleroderma

Diseases and conditions involving the deposition of excessive amounts of collagen include scleroderma, fibrosis, and scar and surgical adhesion formation. Diseases such as scleroderma may result from acute and chronic inflammation, disturbances in the normal parenchymal area, and activation of fibroblasts. ML-05, a modified form of the hemolytic and cytotoxic bacterial toxin, streptolysin O, is being developed for the treatment of such collagen-related disorders. At sublytic concentrations in vitro, ML-05 was shown to activate CD44 expression. This may modulate production of collagen, hyaluronate, and their associated enzymes to allow a restoration of normal extracellular matrices within tissues. More importantly, ML-05 appeared to decrease skin collagen levels in two in vivo models of collagen disorders, the tight skin mouse (Tsk) model of scleroderma, and the bleomycin-induced mouse skin fibrosis model. In the Tsk model, levels of hydroxyproline (a measure of total collagen) decreased by 25% in the Tsk+ML-05 treatment group relative to the Tsk+saline control group over a 3-month period. In the bleomycin-induced skin fibrosis study, hydroxyproline levels decreased from 15–22% over a 6-week period in a bleomycin-induced ML-05 treatment group (relative to levels in a bleomycin-induced, untreated control group). Hydroxyproline levels in samples from this treatment group were only slightly greater than levels in an uninduced control group at 8 weeks. Thus, ML-05 treatment appeared to reduce collagen levels in two separate mouse skin fibrosis models, one genetically based and the other chemically induced

Pharmacodynamics of β-Lactamase Inhibition by NXL104 in Combination with Ceftaroline: Examining Organisms with Multiple Types of β-Lactamases

New broad-spectrum β-lactamases such as KPC enzymes and CTX-M-15 enzymes threaten to markedly reduce the utility of our armamentarium of β-lactam agents, even our most potent drugs, such as carbapenems. NXL104 is a broad-spectrum non-β-lactam β-lactamase inhibitor. In this evaluation, we examined organisms carrying defined β-lactamases and identified doses and schedules of NXL104 in combination with the new cephalosporin ceftaroline, which would maintain good bacterial cell kill and suppress resistance emergence for a clinically relevant period of 10 days in our hollow-fiber infection model. We examined three strains of Klebsiella pneumoniae and one isolate of Enterobacter cloacae. K. pneumoniae 27-908M carried KPC-2, SHV-27, and TEM-1 β-lactamases. Its isogenic mutant, K. pneumoniae 4207J, was “cured” of the plasmid expressing the KPC-2 enzyme. K. pneumoniae 24-1318A carried a CTX-M-15 enzyme, and E. cloacae 2-77C expressed a stably derepressed AmpC chromosomal β-lactamase. Dose-ranging experiments for NXL104 administered as a continuous infusion with ceftaroline at 600 mg every 8 h allowed identification of a 24-h area under the concentration-time curve (AUC) for NXL104 that mediated bactericidal activity and resistance suppression. Dose fractionation experiments identified that “time > threshold” was the pharmacodynamic index linked to cell kill and resistance suppression. Given these results, we conclude that NXL104 combined with ceftaroline on an 8-hourly administration schedule would be optimal for circumstances in which highly resistant pathogens are likely to be encountered. This combination dosing regimen should allow for optimal bacterial cell kill (highest likelihood of successful clinical outcome) and the suppression of resistance emergence

Dose Range Evaluation of Mycograb C28Y Variant, a Human Recombinant Antibody Fragment to Heat Shock Protein 90, in Combination with Amphotericin B-Desoxycholate for Treatment of Murine Systemic Candidiasis ▿

Systemic candidiasis causes significant mortality in patients despite amphotericin B (AMB) therapy. Mycograb C28Y variant, a human recombinant antibody fragment to heat shock protein 90, is closely related to Mycograb, which showed a survival advantage in combination with AMB in a phase III human trial. The Mycograb C28Y variant could potentially increase the antifungal effect of AMB. In our study, the interaction between AMB-desoxycholate (DAMB) and the Mycograb C28Y variant was characterized in vitro by using a checkerboard method. Quantitative cultures of kidneys, livers, and spleens of neutropenic mice with systemic Candida albicans infections were used to assess the in vivo interaction between 1.4 mg/kg of body weight/day of DAMB and 0.15, 1.5, and 15 mg/kg/day of the Mycograb C28Y variant after 1, 3, and 5 days of therapy. DAMB and Mycograb C28Y variant monotherapies, vehicle, and a no-treatment arm served as controls. Also, single- and multidose pharmacokinetics for the Mycograb C28Y variant were determined. Indifference or synergy between DAMB and the Mycograb C28Y variant was seen in two trials by the checkerboard method. The pharmacokinetics of the Mycograb C28Y variant was best described by a 2-compartment model with a median serum t1/2α of ∼0.198 h and a t1/2β of ∼1.77 h. In mice, DAMB together with the Mycograb C28Y variant was no more effective than AMB alone (P > 0.05 by analysis of variance). The Mycograb C28Y variant alone had no antifungal activity. We therefore conclude that the Mycograb C28Y variant in combination with DAMB offered no benefit over DAMB monotherapy in a neutropenic murine model of systemic candidiasis