Pharmacodynamics of taniborbactam in combination with cefepime studied in an in vitro model of infection.

OBJECTIVES: To define the in vitro pharmacodynamics of taniborbactam against Enterobacterales with CTXM-15, KPC, AmpC, and OXA-48 ß-lactamases. METHODS: An in vitro pharmacokinetic model was used to simulate serum concentrations associated with cefepime 2G by 1hr infusion 8hrly. Taniborbactam was given in exposure ranging and fractionation simulations. Reduction in viable count at 24h (Δ 24) was the primary end point and four strains were used: E. coli expressing CTXM-15 or AmpC and K. pneumoniae expressing KPC or OXA-48 enzymes. RESULTS: Taniborbactam was administered as continuous infusions; ≥4 log kill was attained with taniborbactam concentrations of ≥0.01mg/L against CTXM-15 E. coli, ≥0.5mg/L against KPC- and OXA-48 K. pneumoniae, and ≥4mg/L against AmpC E. coli. Analyses were conducted to determine the pharmacokinetic/dynamic driver for each strain. For E. coli (CTXM-15) and E. coli(AmpC), area under the concentration-time curve (AUC) was best related to change in viable count (R20.74 and 0.72, respectively). For K. pneumoniae (KPC) AUC and T>0.25mg/L were equally related to bacterial clearance (R20.72 for both), and for K. pneumoniae (OXA-48) T>0.25mg/L was the best predictor (R20.94). The taniborbactam AUC range to produce a 1-log10 reduction in viable count was 4.4-11.2 mg∙h/L. Analysis of data from all strains indicated T>MIC divided by 4 was best related to change in viable count; however, curve fit was poor R2<0.49. CONCLUSIONS: Taniborbactam was effective in combination with cefepime in producing bacterial clearance for B lactam resistant Enterobacterales. The primary pharmacodynamic driver was AUC or time>threshold, both being closely related to antibacterial effect.

The pharmacodynamics of minocycline alone and in combination with rifampicin against Staphylococcus aureus studied in an in vitro pharmacokinetic model of infection.

BACKGROUND: Tetracyclines are widely used as oral therapy of MRSA infection, however, the pharmacodynamic underpinning is absent. OBJECTIVES: We employed an in vitro pharmacokinetic model to study the pharmacodynamics of minocycline alone and in combination with rifampicin. METHODS: An exposure-ranging design was used to establish fAUC/MIC targets for static, -1 log drop and -2 log drop effects against Staphylococcus aureus for minocycline and in combination with rifampicin. We then simulated 7-10 day human dosing of minocycline and the combination. RESULTS: The minocycline fAUC/MIC for 24 h static effect and -1 log drop in bacterial load were 12.5 ±â€Š7.1 and 23.3 ±â€Š12.4. fAUC/MIC targets for static and -1 log drop were greater at 48 and 72 h. The addition of simulated free rifampicin associated with dosing 300 mg q12h reduced the 24 h minocycline fAUC/MICs. Simulations performed over 7-10 days exposure indicated that for minocycline standard human doses there was a 1-3 log reduction in viable count and no changes in population profiles. Addition of rifampicin resulted in larger reductions in staphylococcal load but emergence of resistance to rifampicin. There was no resistance to minocycline. CONCLUSIONS: An fAUC/MIC minocycline target of 12-36 is appropriate for S. aureus. Addition of rifampicin decreases bacterial load but results in emergence of resistance to rifampicin. Unusually, there was no emergence of resistance to minocycline.

In vitro pharmacodynamics of omadacycline against Escherichia coli and Acinetobacter baumannii.

BACKGROUND: The pharmacodynamics of omadacycline have been extensively studied against Gram-positive pathogens but less information is available for Gram-negative pathogens. We describe the pre-clinical pharmacodynamics of omadacycline against Escherichia coli and Acinetobacter baumannii. METHODS: An in vitro dilutional pharmacokinetic model was used. Exposure experiments with fAUC/MIC ratios ranging from 0 to 1200 were performed using five strains of E. coli and five strains of A. baumannii. Reduction in bacterial load and changes in population profiles were measured. RESULTS: The fAUC/MIC targets against E. coli for 24 h static and -1 log reduction in load were 25.3 ±â€Š17.2 and 42.7 ±â€Š32.5, respectively. For A. baumannii the fAUC/MIC for 24 h static effect was 108.1 ±â€Š38.6. Changes in population profiles were observed for E. coli at fAUC/MIC ratios of ≤200 and for A. baumannii up to 1200. MICs were increased 2-32 fold. CONCLUSIONS: fAUC/MIC targets for A. baumannii are greater than for E.coli and changes in population profiles more likely. E. coli fAUC/MIC targets align with in vivo data and will be useful in determining omadacycline dosing for this pathogen.

Pharmacodynamics of minocycline against Acinetobacter baumannii studied in a pharmacokinetic model of infection.

Minocycline (MNO) is an old antibiotic that may have an important role in the treatment of multidrug-resistant Gram-negative bacterial infections as the burden of such infections increases. In this study, a single-compartment dilutional pharmacokinetic model was used to determine the relationship between MNO exposure and antibacterial effect, including the risk of resistance emergence, against strains of Acinetobacter baumannii. The mean ± standard deviation area under the unbound drug concentration-time curve to minimum inhibitory concentration ratio (fAUC/MIC) associated with a 24-h bacteriostatic effect was 16.4 ± 2.6 and with a -1 log reduction in bacterial load at 24 h was 23.3 ± 3.7. None of the strains reached a -2 log reduction over 48 h. Changes in population profiles were noted for two of the three strains studied, especially at fAUC/MIC ratios of >5-15. A reasonable translational pharmacodynamic target for MNO against A. baumannii could be an fAUC/MIC of 20-25. However, if maximum standard 24-h doses of intravenous MNO are used (400 mg/day), many strains would be exposed to MNO concentrations likely to change population profiles and associated with the emergence of resistance. Either MNO combination therapy or an increased MNO dose (>400 mg/day) should be considered when treating A. baumannii infections.

Comparative antibacterial effects of moxifloxacin and levofloxacin on Streptococcus pneumoniae strains with defined mechanisms of resistance: impact of bacterial inoculum.

OBJECTIVES: We aim to further define the impact of the mechanism of fluoroquinolone resistance and inoculum load on the pharmacodynamic effects of levofloxacin and moxifloxacin on Streptococcus pneumoniae. METHODS: The antibacterial effects of and emergence of resistance (EoR) to moxifloxacin (400 mg once daily) or levofloxacin (750 mg once daily or 500 mg twice daily) were compared using five S. pneumoniae strains containing no known resistance mechanisms, efflux resistance mechanisms, a parC mutation or parC and gyrA mutations, at high (10(8) cfu/mL) and low (10(6) cfu/mL) inocula. An in vitro pharmacokinetic model was used and simulations were performed over 96 h. After drug exposure, isolates were tested for the presence of efflux pumps and mutations in the quinolone resistance-determining regions. RESULTS: A high inoculum diminished the antibacterial effect of moxifloxacin and levofloxacin. Levofloxacin at both dosages produced EoR with all strains. Levofloxacin regimens with AUC/MIC ratios <100 produced EoR. Moxifloxacin produced EoR with the parC strain only. CONCLUSIONS: Levofloxacin dosing regimens with low AUC/MIC ratios select for efflux pump overexpression, leading to fluoroquinolone resistance. Levofloxacin dosing may select for gyrA mutations, inducing moxifloxacin resistance. These data confirm that a fluoroquinolone AUC/MIC ratio of >100 is required for prevention of EoR.

In vitro activities of nine peptide deformylase inhibitors and five comparator agents against respiratory and skin pathogens.

The activity of nine peptide deformylase (PDF) inhibitors undergoing clinical evaluation were compared with co-amoxiclav, levofloxacin, moxifloxacin, erythromycin and telithromycin against a range of respiratory and skin pathogens (n=166). The PDF inhibitor showed good activity against Streptococcus pneumoniae, Moxarella catarrhalis, Group A streptococci and Staphylococcus aureus irrespective of beta-lactam or fluoroquinolone susceptibility. Against Haemophilus influenzae, MIC(90) values were generally higher. BB-88488 was the most active compound. Overall these data suggest that PDF inhibitors are an interesting new class of antimicrobial worthy of further investigation in the treatment of respiratory tract and skin infections.