Pharmacokinetics of isavuconazole at different target sites in healthy volunteers after single and multiple intravenous infusions.

BACKGROUND: Invasive aspergillosis is a severe fungal infection that affects multiple organ systems including the CNS and the lungs. Isavuconazole, a novel triazole antifungal agent, has demonstrated promising activity against Aspergillus spp. However, data on the penetration of isavuconazole into the CNS and ELF and intracellular accumulation remain limited. MATERIALS AND METHODS: We conducted a prospective single-centre pharmacokinetic (PK) study in 12 healthy volunteers. Subjects received seven doses of 200 mg isavuconazole to achieve an assumed steady-state. After the first and final infusion, plasma sampling was conducted over 8 and 12 h, respectively. All subjects underwent one lumbar puncture and bronchoalveolar lavage, at either 2, 6 or 12 h post-infusion of the final dose. PBMCs were collected in six subjects from blood to determine intracellular isavuconazole concentrations at 6, 8 or 12 h. The AUC/MIC was calculated for an MIC value of 1 mg/L, which marks the EUCAST susceptibility breakpoint for Aspergillus fumigatus and Aspergillus flavus. RESULTS: C max and AUC0-24h of isavuconazole in plasma under assumed steady-state conditions were 6.57 ±â€Š1.68 mg/L (mean ±â€ŠSD) and 106 ±â€Š32.1 h·mg/L, respectively. The average concentrations measured in CSF, ELF and in PBMCs were 0.07 ±â€Š0.03, 0.94 ±â€Š0.46 and 27.1 ±â€Š17.8 mg/L, respectively. The AUC/MIC in plasma, CSF, ELF and in PBMCs under steady-state conditions were 106 ±â€Š32.1, 1.68 ±â€Š0.72, 22.6 ±â€Š11.0 and 650 ±â€Š426 mg·h/L, respectively. CONCLUSION: Isavuconazole demonstrated moderate penetration into ELF, low penetrability into CSF and high accumulation in PBMCs. Current dosing regimens resulted in sufficient plasma exposure in all subjects to treat isolates with MICs ≤ 1 mg/L.

Integrative model-based comparison of target site-specific antimicrobial effects: A case study with ceftaroline and lefamulin.

OBJECTIVE: Predictions of antimicrobial effects typically rely on plasma-based pharmacokinetic-pharmacodynamic (PK-PD) targets, ignoring target-site concentrations and potential differences in tissue penetration between antibiotics. In this study, we applied PK-PD modelling to compare target site-specific effects of antibiotics by integrating clinical microdialysis data, in vitro time-kill curves, and antimicrobial susceptibility distributions. As a case study, we compared the effect of lefamulin and ceftaroline against methicillin-resistant Staphylococcus aureus (MRSA) at soft-tissue concentrations. METHODS: A population PK model describing lefamulin concentrations in plasma, subcutaneous adipose and muscle tissue was developed. For ceftaroline, a similar previously reported PK model was adopted. In vitro time-kill experiments were performed with six MRSA isolates and a PD model was developed to describe bacterial growth and antimicrobial effects. The clinical PK and in vitro PD models were linked to compare antimicrobial effects of ceftaroline and lefamulin at the different target sites. RESULTS: Considering minimum inhibitory concentration (MIC) distributions and standard dosages, ceftaroline showed superior anti-MRSA effects compared to lefamulin both at plasma and soft-tissue concentrations. Looking at the individual antibiotics, lefamulin effects were highest at soft-tissue concentrations, while ceftaroline effects were highest at plasma concentrations, emphasising the importance of considering target-site PK-PD in antibiotic treatment optimisation. CONCLUSION: Given standard dosing regimens, ceftaroline appeared more effective than lefamulin against MRSA at soft-tissue concentrations. The PK-PD model-based approach applied in this study could be used to compare or explore the potential of antibiotics for specific indications or in populations with unique target-site PK.

Linezolid brain penetration in neurointensive care patients.

BACKGROUND: Linezolid exposure in critically ill patients is associated with high inter-individual variability, potentially resulting in subtherapeutic antibiotic exposure. Linezolid exhibits good penetration into the CSF, but its penetration into cerebral interstitial fluid (ISF) is unknown. OBJECTIVES: To determine linezolid penetration into CSF and cerebral ISF of neurointensive care patients. PATIENTS AND METHODS: Five neurocritical care patients received 600 mg of linezolid IV twice daily for treatment of extracerebral infections. At steady state, blood and CSF samples were collected from arterial and ventricular catheters, and microdialysate was obtained from a cerebral intraparenchymal probe. RESULTS: The median fAUC0-24 was 57.6 (24.9-365) mg·h/L in plasma, 64.1 (43.5-306.1) mg·h/L in CSF, and 27.0 (10.7-217.6) mg·h/L in cerebral ISF. The median penetration ratio (fAUCbrain_or_CSF/fAUCplasma) was 0.5 (0.25-0.81) for cerebral ISF and 0.92 (0.79-1) for CSF. Cerebral ISF concentrations correlated well with plasma (R = 0.93, P < 0.001) and CSF levels (R = 0.93, P < 0.001).The median fAUC0-24/MIC ratio was ≥100 in plasma and CSF for MICs of ≤0.5 mg/L, and in cerebral ISF for MICs of ≤0.25 mg/L. The median fT>MIC was ≥80% of the dosing interval in CSF for MICs of ≤0.5 mg/L, and in plasma and cerebral ISF for MICs of ≤0.25 mg/L. CONCLUSIONS: Linezolid demonstrates a high degree of cerebral penetration, and brain concentrations correlate well with plasma and CSF levels. However, substantial variability in plasma levels, and thus cerebral concentrations, may result in subtherapeutic tissue concentrations in critically ill patients with standard dosing, necessitating therapeutic drug monitoring.

Target attainment of intravenous lefamulin for treatment of acute bacterial skin and skin structure infections.

OBJECTIVES: Lefamulin is a pleuromutilin antibiotic approved for the treatment of community-acquired bacterial pneumonia (CABP). Its spectrum of activity, good penetration into soft tissues and low rates of cross-resistance also make lefamulin a potentially valuable option for treatment of acute bacterial skin and skin structure infections (ABSSSIs). A Phase 2 trial of lefamulin for ABSSSI indicated similar efficacy of 100 and 150 mg q12h IV dosing regimens. In the present study, the potential of lefamulin for this indication was further evaluated from a translational pharmacokinetic/pharmacodynamic perspective. METHODS: PTA was determined for various dosages using Monte Carlo simulations of a population pharmacokinetic model of lefamulin in ABSSSI patients and preclinical exposure targets associated with bacteriostasis and a 1-log reduction in bacterial count. Overall target attainment against MSSA and MRSA was calculated using lefamulin MIC distributions. RESULTS: Overall attainment of the bacteriostasis target was 94% against MSSA and 84% against MRSA for the IV dosage approved for CABP (150 mg q12h). Using the same target, for the 100 mg q12h regimen, overall target attainment dropped to 68% against MSSA and 50% against MRSA. Using the 1-log reduction target, overall target attainment for both regimens was <40%. CONCLUSIONS: Lefamulin at the currently approved IV dosage covers most Staphylococcus aureus isolates when targeting drug exposure associated with bacteriostasis, suggesting potential of lefamulin for the treatment of ABSSSIs. Lefamulin may not be appropriate in ABSSSI when rapid bactericidal activity is warranted.

Plasma and intraperitoneal pharmacokinetics of ceftazidime/avibactam in peritoneal dialysis patients.

OBJECTIVES: Peritonitis is a serious complication in patients undergoing automated peritoneal dialysis (APD) that increases morbidity and frequently disqualifies patients from the peritoneal dialysis programme. Ceftazidime/avibactam (CAZ/AVI) is a potential treatment option for APD patients with peritonitis caused by resistant Gram-negative bacteria, but limited data exist on systemic and target-site pharmacokinetics (PK) in patients undergoing APD. This study set out to investigate the PK of CAZ/AVI in plasma and peritoneal dialysate (PDS) of patients undergoing APD. METHODS: A prospective, open-label PK study was conducted on eight patients undergoing APD. CAZ/AVI was administered as a single intravenous dose of 2 g/0.5 g over 120 minutes. APD cycles were initiated 15 hours after the study drug administration. Dense PDS and plasma sampling was performed for 24 hours after the start of administration. PK parameters were analysed with population PK modelling. Probability of target attainment (PTA) was simulated for different CAZ/AVI doses. RESULTS: PK profiles of both drugs in plasma and PDS were similar, indicating that the two drugs are well suited for a fixed-dose combination. A two-compartment model best described the PK of both drugs. A single dose of 2 g/0.5 g CAZ/AVI led to concentrations that far exceeded the PK/PD targets of both drugs. In the Monte Carlo simulations, even the lowest dose (750/190 mg CAZ/AVI) achieved a PTA of >90% for MICs up to 8 mg/L (The European Committee on Antimicrobial Susceptibility Testing epidemiological cut-off value for Pseudomonas aeruginosa) in plasma and PDS. DISCUSSION: On the basis of PTA simulations, a dose of 750/190 mg CAZ/AVI would be sufficient to treat plasma and peritoneal fluid infections in patients undergoing APD.

Bacterial growth and ceftriaxone activity in individual ascitic fluids in an in vitro model of spontaneous bacterial peritonitis.

Introduction: The environment of the infection site affects bacterial growth and antibiotic activity. When bacterial growth and antibiotic activity are studied in body fluids, samples of multiple subjects are usually pooled, averaging out potentially relevant differences in composition. The ascitic fluid (AF) environment is frequently associated with spontaneous bacterial peritonitis (SBP) in cirrhotic patients. In this study, bacterial growth and ceftriaxone activity were evaluated in individual AF using an in vitro model of SBP, reflecting the environment and pharmacokinetics at the infection site. Methods: AF was obtained from nine cirrhotic patients with non-infected ascites. Growth of nine bacterial strains (three Escherichia coli, four Staphylococcus aureus, one Enterococcus faecalis, and one Klebsiella pneumoniae) in individual AF was assessed and correlated with biomarkers including potential risk factors for SBP. Ceftriaxone time-kill experiments, in which the pharmacokinetic profile observed in AF following a 1 g intravenous infusion was replicated, were performed with two E. coli and two S. aureus isolates with minimum inhibitory concentrations around the ceftriaxone resistance breakpoint. Results: Significant correlations were found between bacterial growth and AF levels of protein (Spearman's rank correlation coefficient ρ = -0.35), albumin (ρ = -0.31), and complement C3c (ρ = -0.28), and serum levels of bilirubin (ρ = 0.39) and aspartate aminotransferase (ρ = 0.25). Ceftriaxone was active in AF, even against resistant isolates, generally resulting in ≥2 log reductions in bacterial count within 24 h. Conclusion: Ascites patients may be predisposed to or protected against SBP based on the antimicrobial capacity of their AF. Ceftriaxone at clinical AF concentrations is active in the AF environment.

Comparison of ultrafiltration and microdialysis for ceftriaxone protein-binding determination.

BACKGROUND: High protein binding (PB) of antibiotics has an impact on their antimicrobial activity. It has been questioned whether in vitro PB determination can capture the dynamic and concentration-dependent PB of highly bound antibiotics. OBJECTIVES: This clinical study compared in vitro ultrafiltration (UF) and in vivo IV microdialysis (MD) methods to determine ceftriaxone PB. METHODS: Six healthy male volunteers received a single IV 2 g dose of ceftriaxone. Unbound ceftriaxone plasma concentrations were measured with MD and venous plasma sampling with subsequent UF. Pharmacokinetic parameters were determined using non-compartmental pharmacokinetic analysis. Non-linear mixed-effects modelling was used to quantify the PB. The PTA was estimated. RESULTS: The Cmax of ceftriaxone total plasma concentration (297.42 ±â€Š21.0 mg/L) was approximately 5.5-fold higher than for free concentrations obtained with UF (52.83 ±â€Š5.07 mg/L), and only 3.5-fold higher than for free concentrations obtained with MD (81.37 ±â€Š26.93 mg/L). Non-linear, saturable PB binding was confirmed for both UF and MD. Significantly different dissociation constants (Kd) for the albumin/ceftriaxone complex were quantified: in UF it was 23.7 mg/L (95% CI 21.3-26.2) versus 15.9 mg/L (95% CI 13.6-18.6) in MD. Moreover, the estimated number of binding sites (95% CI) per albumin molecule was 0.916 (0.86-0.97) in UF versus 0.548 in MD (0.51-0.59). The PTA obtained with MD was at most 27% higher than with UF. CONCLUSIONS: In vitro UF versus in vivo intravasal MD revealed significantly different PB, especially during the distribution phase. The method of PB determination could have an impact on the breakpoint determination and dose optimisation of antibiotics.

Targeted temperature management after cardiac arrest is associated with reduced metabolism of pantoprazole - A probe drug of CYP2C19 metabolism.

OBJECTIVE: Targeted temperature management (TTM) is part of standard post-resuscitation care. TTM may downregulate cytochrome enzyme activity and thus impact drug metabolism. This study compared the pharmacokinetics (PK) of pantoprazole, a probe drug of CYP2C19-dependent metabolism, at different stages of TTM following cardiac arrest. METHODS: This prospective controlled study was performed at the Medical University of Vienna and enrolled 16 patients following cardiac arrest. The patients completed up to three study periods (each lasting 24 h) in which plasma concentrations of pantoprazole were quantified: (P1) hypothermia (33 °C) after admission, (P2) normothermia after rewarming (36 °C, intensive care), and (P3) normothermia during recovery (normal ward, control group). PK was analysed using non-compartmental analysis and nonlinear mixed-effects modelling. RESULTS: 16 patients completed periods P1 and P2; ten completed P3. The median half-life of pantoprazole was 2.4 h (quartiles: 1.8-4.8 h) in P1, 2.8 h (2.1-6.8 h, p = 0.046 vs. P1, p = 0.005 vs. P3) in P2 and 1.2 h (0.9 - 2.3 h, p = 0.007 vs. P1) in P3. A two-compartment model described the PK data best. Typical values for clearance were estimated separately for each study period, indicating 40% and 29% reductions during P1 and P2, respectively, compared to P3. The central volume of distribution was estimated separately for P2, indicating a 64% increase compared to P1 and P3. CONCLUSION: CYP2C19-dependent drug metabolism is downregulated during TTM following cardiac arrest. These results may influence drug choice and dosing of similarly metabolized drugs and may be helpful for designing studies in similar clinical situations.

Predicting Antimicrobial Activity at the Target Site: Pharmacokinetic/Pharmacodynamic Indices versus Time-Kill Approaches.

Antibiotic dosing strategies are generally based on systemic drug concentrations. However, drug concentrations at the infection site drive antimicrobial effect, and efficacy predictions and dosing strategies should be based on these concentrations. We set out to review different translational pharmacokinetic-pharmacodynamic (PK/PD) approaches from a target site perspective. The most common approach involves calculating the probability of attaining animal-derived PK/PD index targets, which link PK parameters to antimicrobial susceptibility measures. This approach is time efficient but ignores some aspects of the shape of the PK profile and inter-species differences in drug clearance and distribution, and provides no information on the PD time-course. Time-kill curves, in contrast, depict bacterial response over time. In vitro dynamic time-kill setups allow for the evaluation of bacterial response to clinical PK profiles, but are not representative of the infection site environment. The translational value of in vivo time-kill experiments, conversely, is limited from a PK perspective. Computational PK/PD models, especially when developed using both in vitro and in vivo data and coupled to target site PK models, can bridge translational gaps in both PK and PD. Ultimately, clinical PK and experimental and computational tools should be combined to tailor antibiotic treatment strategies to the site of infection.