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Antibiotic development traditionally involved large Phase 3 programs, preceded by Phase 2 studies. Recognizing the high unmet medical need for new antibiotics and, in some cases, challenges to conducting large clinical trials, regulators created a streamlined clinical development pathway in which a lean clinical efficacy dataset is complemented by nonclinical data as supportive evidence of efficacy. In this context, translational Pharmacokinetic/Pharmacodynamic (PK/PD) plays a key role and is a major contributor to a "robust" nonclinical package. The classical PK/PD index approach, proven successful for established classes of antibiotics, is at the core of recent antibiotic approvals and the current antibacterial PK/PD guidelines by regulators. Nevertheless, in the case of novel antibiotics with a novel Mechanism of Action (MoA), there is no prior experience with the PK/PD index approach as the basis for translating nonclinical efficacy to clinical outcome, and additional nonclinical studies and PK/PD analyses might be considered to increase confidence. In this review, we discuss the value and limitations of the classical PK/PD approach and present potential risk mitigation activities, including the introduction of a semi-mechanism-based PK/PD modeling approach. We propose a general nonclinical PK/PD package from which drug developers might choose the studies most relevant for each individual candidate in order to build up a "robust" nonclinical PK/PD understanding. [ABSTRACT FROM AUTHOR]

Time-kill curves (TKCs) are more informative compared with the use of minimum inhibitory concentration (MIC) as they allow the capture of bacterial growth and the development of drug killing rates over time, which allows to compute key pharmacodynamic (PD) parameters. Our study aimed, using a semi-mechanistic mathematical model, to estimate the best pharmacokinetic/pharmacodynamic (PK/PD) indices (ƒAUC/MIC or %ƒT > MIC) for the prediction of clinical efficacy of veterinary FQs in Staphylococcus pseudintermedius, Staphylococcus aureus, and Escherichia coli collected from canine pyoderma cases with a focus on the comparison between marbofloxacin and pradofloxacin. Eight TCKs for each bacterial species (4 susceptible and 4 resistant) were analysed in duplicate. The best PK/PD index was ƒAUC24h/MIC in both staphylococci and E. coli. For staphylococci, values of 25–40 h were necessary to achieve a bactericidal effect, whereas the calculated values (25–35 h) for E. coli were lower than those predicting a positive clinical outcome (100–120 h) in murine models. Pradofloxacin showed a higher potency (lower EC50) in comparison with marbofloxacin. However, no difference in terms of a maximal possible pharmacological killing rate (Emax) was observed. Taking into account in vivo exposure at the recommended dosage regimen (3 and 2 mg/kg for pradofloxacin and marbofloxacin, respectively), the overall killing rates (Kdrug) computed were also similar in most instances. [ABSTRACT FROM AUTHOR]

Antibiotic development traditionally involved large Phase 3 programs, preceded by Phase 2 studies. Recognizing the high unmet medical need for new antibiotics and, in some cases, challenges to conducting large clinical trials, regulators created a streamlined clinical development pathway in which a lean clinical efficacy dataset is complemented by nonclinical data as supportive evidence of efficacy. In this context, translational Pharmacokinetic/Pharmacodynamic (PK/PD) plays a key role and is a major contributor to a “robust” nonclinical package. The classical PK/PD index approach, proven successful for established classes of antibiotics, is at the core of recent antibiotic approvals and the current antibacterial PK/PD guidelines by regulators. Nevertheless, in the case of novel antibiotics with a novel Mechanism of Action (MoA), there is no prior experience with the PK/PD index approach as the basis for translating nonclinical efficacy to clinical outcome, and additional nonclinical studies and PK/PD analyses might be considered to increase confidence. In this review, we discuss the value and limitations of the classical PK/PD approach and present potential risk mitigation activities, including the introduction of a semi-mechanism-based PK/PD modeling approach. We propose a general nonclinical PK/PD package from which drug developers might choose the studies most relevant for each individual candidate in order to build up a “robust” nonclinical PK/PD understanding.

For decades, flucloxacillin has been used to treat methicillin-susceptible Staphylococcus aureus (MSSA). Little is still known about its pharmacodynamics (PD). The present study aimed to determine the pharmacokinetic (PK)/PD index and the PD-index value minimally required for efficacy. MICs of 305 MSSA isolates were measured to determine the wild-type distribution. The PD of 8 S. aureus, 1 S. pyogenes, and 1 S. agalactiae isolates were evaluated in a neutropenic murine thigh infection model. Two S. aureus isolates were used in a dose-fractionation study and a dose–response analysis was performed additionally in the in vivo model. Data were analyzed with a population PK and sigmoid maximum effect model. The end of the wild-type distribution was 1 mg/L. The percentage of time the unbound concentration was above MIC (%fT > MIC) was best correlated with efficacy. For S. aureus, median %fT > 0.25 × MIC required for 1-log reduction was 15%. The value for S. pyogenes was 10%fT > MIC and for S. agalactiae 22%fT > 0.25xMIC for a 1-log reduction. The effect of flucloxacillin reached a 2-log reduction of S. aureus at 20%fT > 0.25xMIC and also for S. pyogenes and S. agalactiae, a reduction was reached. These data may serve to optimize dosing regimens currently used in humans. [ABSTRACT FROM AUTHOR]

Pharmacokinetic-pharmacodynamic (PKPD) models have met increasing interest as tools to identify potential efficacious antibiotic dosing regimens in vitro and in vivo. We sought to investigate the impact of diversely shaped clinical pharmacokinetic profiles of meropenem on the growth/killing patterns of Pseudomonas aeruginosa (ARU552, MIC = 16 mg/L) over time using a semi-mechanistic PKPD model and a PK/PD index-based approach. Bacterial growth/killing were driven by the PK profiles of six patient populations (infected adults, burns, critically ill, neurosurgery, obese patients) given varied pathogen features (e.g., EC50, growth rate, inoculum), patient characteristics (e.g., creatinine clearance), and ten dosing regimens (including two dose levels and 0.5-h, 3-h and continuous-infusion regimens). Conclusions regarding the most favourable dosing regimen depended on the assessment of (i) the total bacterial load or fT>MIC (time that unbound concentrations exceed the minimum inhibitory concentration); (ii) the median or P0.95 profile of the population; and (iii) 8 h or 24 h time points. Continuous infusion plus loading dose as well as 3-h infusions (3-h infusions: e.g., for scenarios associated with low meropenem concentrations, P0.95 profiles, and MIC ≥ 16 mg/L) appeared superior to standard 0.5-h infusions at 24 h. The developed platform can serve to identify promising strategies of efficacious dosing for clinical trials. [ABSTRACT FROM AUTHOR]

For decades, flucloxacillin has been used to treat methicillin-susceptible Staphylococcus aureus (MSSA). Little is still known about its pharmacodynamics (PD). The present study aimed to determine the pharmacokinetic (PK)/PD index and the PD-index value minimally required for efficacy. MICs of 305 MSSA isolates were measured to determine the wild-type distribution. The PD of 8 S. aureus, 1 S. pyogenes, and 1 S. agalactiae isolates were evaluated in a neutropenic murine thigh infection model. Two S. aureus isolates were used in a dose-fractionation study and a dose–response analysis was performed additionally in the in vivo model. Data were analyzed with a population PK and sigmoid maximum effect model. The end of the wild-type distribution was 1 mg/L. The percentage of time the unbound concentration was above MIC (%fT > MIC) was best correlated with efficacy. For S. aureus, median %fT > 0.25 × MIC required for 1-log reduction was 15%. The value for S. pyogenes was 10%fT > MIC and for S. agalactiae 22%fT > 0.25xMIC for a 1-log reduction. The effect of flucloxacillin reached a 2-log reduction of S. aureus at 20%fT > 0.25xMIC and also for S. pyogenes and S. agalactiae, a reduction was reached. These data may serve to optimize dosing regimens currently used in humans.

Temocillin is used for the treatment of various infections caused by Enterobacterales . The pharmacokinetic (PK)/pharmacodynamic (PD) index that is best correlated with the activity of beta-lactams is the percentage of time that the unbound concentration exceeds the MIC (% f T>MIC). However, the % f T>MIC needed for a bacteriostatic or killing effect of temocillin is unknown in thigh and lung infection models. In the present study, we studied the temocillin PK in plasma and epithelial lining fluid (ELF) of infected neutropenic mice and determined the plasma exposure-response relationships for Escherichia coli and Klebsiella pneumoniae. Neutropenic murine thigh and lung infection models were used. The bacterial loads in the thighs or lungs were determined. A sigmoid maximum-effect model was used to fit the plasma exposure-response relationship. A one-compartment model with first-order absorption best described temocillin PK (clearance [CL], 1.03 L/h/kg; volume of distribution [ V ], 0.457 L/kg). Protein binding was 78.2% ± 1.3% across different plasma concentrations. A static effect was achieved for all strains in both the thigh and lung infection models. However, the median % f T>MIC needed for a static effect was much lower in the lung infection model (27.8% for E. coli and 38.2% for K. pneumoniae) than in the thigh infection model (65.2% for E. coli and 64.9% for K. pneumoniae). A 1-log kill was reached for all strains in the lung infection model (median % f T>MIC values of 42.1% for E. coli and 44.1% for K. pneumoniae) and 7 out of 8 strains in the thigh infection model (median % f T>MIC values of 85.4% for E. coli and 74.5% for K. pneumoniae). These data support the use of temocillin in patients with pneumonia.

Combination therapy with ampicillin plus ceftriaxone (AMP+CRO) is the first-line therapy for treating severe infections due to Enterococcus faecalis. However, the pharmacokinetic/pharmacodynamic (PK/PD) index linked to the in vivo efficacy of the combination is not yet defined, hindering dose optimization in the clinic. Because classical PK/PD indices are not directly applicable to antimicrobial combinations, two novel indices were tested in the optimized murine model of infection by E. faecalis to delineate the potentiation of AMP by CRO: the time above the CRO threshold (T >threshold ) and the time above the AMP instantaneous MIC (T >MICi ). The potential clinical relevance was evaluated by simulating human doses of AMP and CRO. Hill's equation fitted well the exposure-response data in terms of T >threshold , with a CRO threshold of 1 mg/L. The required exposures were 46%, 49%, and 52% for stasis and 1- and 2-log 10 killing, respectively. Human ceftriaxone doses of 2 g every 12 h (q12h) would reach the target in >90% of strains with thresholds ≤64 mg/L. The AMP T >MICi index also fitted well, and the required exposures were 37%, 41%, and 46% for stasis and 1- and 2-log 10 killing, respectively. In humans, the addition of CRO would allow use of lower AMP doses to reach the same T >MICi and to treat strains with higher MICs. This is the first report of the PK/PD indices and required magnitudes linked to AMP+CRO against E. faecalis; these results can be used as the basis to guide the design of clinical trials to improve combined therapy against enterococci.

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Background: Dicloxacillin, a semisynthetic isoxazolyl penicillin, exhibits antimicrobial activity against a wide variety of Gram-positive bacteria, as well as stability against penicillinases and low level of toxicity. The objective of this study was to obtain optimal dosing regimen of oral administration of dicloxacillin by analyzing the pharmacokinetic (PK) index in healthy volunteers and in vitro antibacterial activity by using Monte Carlo simulation., Materials and Methods: A total of 867 clinical isolates from community-onset infections were collected from 31 secondary hospitals in People's Republic of China. The minimum inhibitory concentration (MIC) values of dicloxacillin were determined by the agar dilution method. Based on the MICs and the PK parameters of different dosage regimens, Monte Carlo simulation was performed to simulate the PK/pharmacodynamic indices of 250 mg once-daily (qd), 500 mg qd, 1,000 mg qd, 2,000 mg qd, 250 mg every 6 hours (q6h), and 500 mg q6h, respectively. The probability of target attainment was estimated at each MIC value, and the cumulative fraction of response (CFR) was calculated to evaluate the efficacy of these regimens., Results: Dicloxacillin showed poor antibacterial activity against Haemophilus influenzae , Moraxella catarrhalis , and Streptococcus pneumoniae . Resistance to dicloxacillin was observed in 7.5% of coagulase-negative Staphylococcus (CNS) isolates and 9.2% of other Streptococcus isolates, whereas 1.5% of methicillin-sensitive Staphylococcus aureus (MSSA) was resistant to dicloxacillin. Multiple-dose regimens could obtain higher CFR than single-dose regimens against H. influenza and S. pneumoniae . However, all dosing regimens against MSSA achieved CFR ≥$90%. Meanwhile, dosing regimen of 2,000 mg qd, 250 mg q6h, and 500 mg q6h could achieve >90% of CFR for CNS. For other Streptococcus isolates, multiple-dose regimens achieved CFR ≥90%., Conclusion: Dicloxacillin has a significant antibacterial activity against MSSA, CNS, and other Streptococcus isolates. The simulation results suggest that dicloxacillin 250 mg q6h and 500 mg q6h dosing regimens may be recommended for clinical applications, especially for community-onset infections., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: β-lactams are among the most frequently prescribed antibiotics for the treatment of neonatal sepsis. Survival of extremely preterm neonates necessitates an improved understanding of how β-lactams should be used in this vulnerable population. Appropriate dosing regimens for neonates remain unclear. We reviewed available data on the pharmacokinetics (PK) of β -lactam drugs in neonates. Pharmacokinetic/ pharmacodynamic (PK/PD) efficacy index surrogates and minimum inhibitory concentrations (MICs) used to support dosing regimens recommendation in the studies were also investigated., Methods: A comprehensive literature search was undertaken to identify studies that have investigated the PK/PD of β-lactam drugs in neonates., Results: Data available for the PK/PD of β-lactams in neonates are limited but confirm the importance of weight, gestational age and postnatal age as markers of growth and renal maturation. The contribution of tubular secretion in addition to glomerular filtration is highlighted. The development of methods to assay β-lactam protein binding in vivo has added greater understanding. Modelling and simulation techniques have aided dosing optimisation. However, there remains a gap in the understanding of PD parameters and the appropriate PK/PD index to target for improved clinical outcome which partly explains the various dosing recommendations. Improved data on the efficacy of β -lactams are needed in a context of increasing global antimicrobial resistance and variable geographic MIC distribution., Conclusion: Prospective in vivo studies are required to validate PK/PD indexes associated with clinical efficacy. Current antimicrobial stewardship efforts should integrate PK/PD principles and dosing optimization, taking into account susceptibility of isolated microorganisms., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)