Optimization and evaluation of piperacillin plus tobramycin combination dosage regimens againstfor patients with altered pharmacokineticsthe hollow-fiber infection model and mechanism-based modeling

Augmented renal clearance (ARC) in critically-ill patients can result in suboptimal drug exposures and treatment failure. Combination dosage regimens accounting for ARC have never been optimized and evaluated againstusing the hollow-fiber infection model (HFIM). Using aisolate from a critically-ill patient and static concentration time-kill experiments (SCTK), we studied clinically relevant piperacillin and tobramycin concentrations, alone and in combinations, at two inocula (10and 10CFU/mL) over 72h. We subsequently evaluated the effect of optimized piperacillin (4 g q4h, 0.5h infusion) plus tobramycin (5 mg/kg q24h, 7 mg/kg q24h and 10 mg/kg q48h as 0.5h infusions) regimens on killing and regrowth in the HFIM, simulating a creatinine clearance of 250 mL/min. Mechanism-based modeling was performed in S-ADAPT. In SCTKs, piperacillin plus tobramycin (except combinations with 8 mg/liter tobramycin at low inoculum) achieved synergistic killing (≥2 logthe most active monotherapy at 48h and 72h) and prevented regrowth. Piperacillin monotherapy (4 g q4h) in the HFIM provided 2.4 loginitial killing followed by regrowth at 24h with resistance emergence. Tobramycin monotherapies displayed rapid initial killing (≥5 logat 13h) followed by extensive regrowth. As predicted by mechanism-based modeling, the piperacillin plus tobramycin dosage regimens were synergistic and provided ≥5 logkilling with resistance suppression over 8 days in the HFIM. Optimized piperacillin plus tobramycin regimens provided significant bacterial killing and suppressed resistance emergence. These regimens appear highly promising for effective and early treatment, even in the near-worst case scenario of ARC

Innovative, translational, mechanism-based modelling approach to rationally optimise patient therapy

The increasing prevalence of infections caused by multidrug-resistant Gram-negative ‘superbugs’ is emerging as one of the most significant threats to human health. In the face of the dire shortage of new antibiotics and rapid emergence of resistance during monotherapy, rationally designed combinations of available antibiotics are a highly promising option to combat this global threat. This thesis combines experimental models, mechanism-based modelling and Monte Carlo simulations using human population pharmacokinetics to optimise combination therapies for specific patient populations. The application of the approach developed in this thesis has significant potential to optimise clinical regimens, and ultimately save patient lives

Prescription Pattern of Antihypertensive Agents in T2DM Patients Visiting Tertiary Care Centre in North India

Background. Hypertension management is of a paramount importance in diabetic patients for cardiovascular risk reduction. Aim. To evaluate prescribing pattern of antihypertensive in T2DM (type 2 diabetes) patients and compare with existing recent guidelines. Methods. A cross-sectional study involving evaluation of all T2DM patients referred to endocrinology unit at tertiary care centre for hypertension, comorbid complications, and recording prescription. Utilization of 5 different antihypertensive drug classes was compared for all patients receiving 1, 2, 3, 4, or more drugs. Logistical regression was used to assess likelihood of prescription of drugs and/or therapy for specific conditions mentioned in the guidelines. Results. Out of 1358, T2DM enrolled patients 1186 (87%) had hypertension (males 52%, females 48%). The median duration (IQ) of hypertension diabetics was 4 (1–10) years. A total of 25% patients had controlled BP and 75% with uncontrolled blood pressure (13% isolated systolic hypertension, 6% isolated diastolic hypertension, and 55% both elevated). Overall, ACE inhibitors (ACEIs) were prescribed the highest (59%) followed by angiotensin receptor blockers (ARBs) (52%), calcium channel blockers (CCBs) (29%), diuretics (27%), and beta-blockers (14%). Overall, 55% of T2DM patients were on polytherapy, 41% on monotherapy, and 4% had no antihypertensive treatment. Polytherapy was more predominant with age, duration of diabetes, duration of hypertension, and comorbid complications. Conclusion. Although prescribing pattern of antihypertensive showed adherence to existing evidence-based guidelines, higher proportion of uncontrolled hypertensive patients was found

Evaluation of pharmacokinetic/pharmacodynamic model-based optimized combination regimens against multidrug-resistant Pseudomonas aeruginosa in a murine thigh infection model by using humanized dosing schemes

ABSTRACT We previously optimized imipenem and tobramycin combination regimens against a double-resistant clinical Pseudomonas aeruginosa isolate by using in vitro infection models, mechanism-based pharmacokinetic/pharmacodynamic modeling (MBM), and Monte Carlo simulations. The current study aimed to evaluate these regimens in a neutropenic murine thigh infection model and to characterize the time course of bacterial killing and regrowth via MBM. We studied monotherapies and combinations of imipenem with tobramycin in vivo against the double-resistant clinical P. aeruginosa isolate by using humanized dosing schemes. Viable count profiles of total and resistant populations were quantified over 24 h. Tobramycin monotherapy (7 mg/kg every 24 h [q24h] as a 0.5-h infusion) was ineffective. Imipenem monotherapies (continuous infusion of 4 or 5 g/day with a 1-g loading dose) yielded 2.47 or 2.57 log 10 CFU/thigh killing at 6 h. At 24 h, imipenem at 4 g/day led to regrowth up to the initial inoculum (4.79 ± 0.26 log 10 CFU/thigh), whereas imipenem at 5 g/day displayed 1.75 log 10 killing versus the initial inoculum. The combinations (i.e., imipenem at 4 or 5 g/day plus tobramycin) provided a clear benefit, with bacterial killing of ≥2.51 or ≥1.50 log 10 CFU/thigh compared to the respective most active monotherapy at 24 h. No colonies were detected on 3×MIC agar plates for combinations, whereas increased resistance (at 3×MIC) emerged for monotherapies (except imipenem at 5 g/day). MBM suggested that tobramycin considerably enhanced the imipenem target site concentration up to 2.6-fold. The combination regimens, rationally optimized via a translational modeling approach, demonstrated substantially enhanced bacterial killing and suppression of regrowth in vivo against a double-resistant isolate and are therefore promising for future clinical evaluation. </jats:p

Novel approach to optimize synergistic carbapenem-aminoglycoside combinations against carbapenem-resistant <i>Acinetobacter baumannii</i>

Acinetobacter baumannii is among the most dangerous pathogens and emergence of resistance is highly problematic. Our objective was to identify and rationally optimize β-lactam-plus-aminoglycoside combinations via novel mechanism-based modeling that synergistically kill and prevent resistance of carbapenem-resistant A. baumannii. We studied combinations of 10 β-lactams and three aminoglycosides against four A. baumannii strains, including two imipenem-intermediate (MIC, 4 mg/liter) and one imipenem-resistant (MIC, 32 mg/liter) clinical isolate, using high-inoculum static-concentration time-kill studies. We present the first application of mechanism-based modeling for killing and resistance of A. baumannii using Monte Carlo simulations of human pharmacokinetics to rationally optimize combination dosage regimens for immunocompromised, critically ill patients. All monotherapies achieved limited killing (≤2.3 log(10)) of A. baumannii ATCC 19606 followed by extensive regrowth for aminoglycosides. Against this strain, imipenem-plus-aminoglycoside combinations yielded more rapid and extensive killing than other β-lactam-plus-aminoglycoside combinations. Imipenem at 8 mg/liter combined with an aminoglycoside yielded synergistic killing (>5 log(10)) and prevented regrowth of all four strains. Modeling demonstrated that imipenem likely killed the aminoglycoside-resistant population and vice versa and that aminoglycosides enhanced the target site penetration of imipenem. Against carbapenem-resistant A. baumannii (MIC, 32 mg/liter), optimized combination regimens (imipenem at 4 g/day as a continuous infusion plus tobramycin at 7 mg/kg of body weight every 24 h) were predicted to achieve >5 log(10) killing without regrowth in 98.2% of patients. Bacterial killing and suppression of regrowth were best achieved for combination regimens with unbound imipenem steady-state concentrations of at least 8 mg/liter. Imipenem-plus-aminoglycoside combination regimens are highly promising and warrant further evaluation

Aminoglycoside concentrations required for synergy with carbapenems against <i>Pseudomonas aeruginosa</i> determined via mechanistic studies and modeling

ABSTRACT This study aimed to systematically identify the aminoglycoside concentrations required for synergy with a carbapenem and characterize the permeabilizing effect of aminoglycosides on the outer membrane of Pseudomonas aeruginosa . Monotherapies and combinations of four aminoglycosides and three carbapenems were studied for activity against P. aeruginosa strain AH298-GFP in 48-h static-concentration time-kill studies (SCTK) (inoculum: 10 7.6 CFU/ml). The outer membrane-permeabilizing effect of tobramycin alone and in combination with imipenem was characterized via electron microscopy, confocal imaging, and the nitrocefin assay. A mechanism-based model (MBM) was developed to simultaneously describe the time course of bacterial killing and prevention of regrowth by imipenem combined with each of the four aminoglycosides. Notably, 0.25 mg/liter of tobramycin, which was inactive in monotherapy, achieved synergy (i.e., ≥2-log 10 more killing than the most active monotherapy at 24 h) combined with imipenem. Electron micrographs, confocal image analyses, and the nitrocefin uptake data showed distinct outer membrane damage by tobramycin, which was more extensive for the combination with imipenem. The MBM indicated that aminoglycosides enhanced the imipenem target site concentration up to 4.27-fold. Tobramycin was the most potent aminoglycoside to permeabilize the outer membrane; tobramycin (0.216 mg/liter), gentamicin (0.739 mg/liter), amikacin (1.70 mg/liter), or streptomycin (5.19 mg/liter) was required for half-maximal permeabilization. In summary, our SCTK, mechanistic studies and MBM indicated that tobramycin was highly synergistic and displayed the maximum outer membrane disruption potential among the tested aminoglycosides. These findings support the optimization of highly promising antibiotic combination dosage regimens for critically ill patients. </jats:p

A Phase 1a Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of RO7303509, an Anti-TGFβ3 Antibody, in Healthy Volunteers

Abstract Introduction Transforming growth factor beta (TGFβ) cytokines (TGFβ1, TGFβ2, and TGFβ3) play critical roles in tissue fibrosis. However, treatment with systemic pan-TGFβ inhibitors have demonstrated unacceptable toxicities. In this study, we evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of RO7303509, a high-affinity, TGFβ3-specific, humanized immunoglobulin G1 monoclonal antibody, in healthy adult volunteers (HVs). Methods This phase 1a, randomized, double-blind trial included six cohorts for evaluation, with each cohort receiving single doses of placebo or RO7303509, administered intravenously (IV; 50 mg, 150 mg, 240 mg) or subcutaneously (SC; 240 mg, 675 mg, 1200 mg). The frequency and severity of adverse events (AEs) and RO7303509 serum concentrations were monitored throughout the study. We also measured serum periostin and cartilage oligomeric matrix protein (COMP) by immunoassay and developed a population pharmacokinetics model to characterize RO7303509 serum concentrations. Results The study enrolled 49 HVs, with a median age of 39 (range 18–73) years. Ten (27.8%) RO7303509-treated subjects reported 24 AEs, and six (30.8%) placebo-treated subjects reported six AEs. The most frequent AEs related to the study drug were injection site reactions and infusion-related reactions. Maximum serum concentrations (C max) and area under the concentration–time curve from time 0 to infinity (AUC0–inf) values for RO7303509 appeared to increase dose-proportionally across all doses tested. Serum concentrations across cohorts were best characterized by a two-compartment model plus a depot compartment with first-order SC absorption kinetics. No subjects tested positive for anti-drug antibodies (ADAs) at baseline; one subject (2.8%; 50 mg IV) tested positive for ADAs at a single time point (day 15). No clear pharmacodynamic effects were observed for periostin or COMP upon TGFβ3 inhibition. Conclusion RO7303509 was well tolerated at single SC doses up to 1200 mg in HVs with favorable pharmacokinetic data that appeared to increase dose-proportionally. TGFβ3-specific inhibition may be suitable for development as a chronic antifibrotic therapy. Trial Registration ISRCTN13175485

Wandel in Feldbaumethoden und Ackerwildkrautflora im Raum Ingolstadt während der letzten 3 Jahrzehnte

Bacterial resistance is among the most serious threats to human health globally, and many bacterial isolates have emerged that are resistant to all antibiotics in monotherapy. Aminoglycosides are often used in combination therapies against severe infections by multidrug-resistant bacteria. However, models quantifying different antibacterial effects of aminoglycosides are lacking. While the mode of aminoglycoside action on protein synthesis has often been studied, their disruptive action on the outer membrane of Gram-negative bacteria remains poorly characterized. Here, we developed a novel quantitative model for these two mechanisms of aminoglycoside action, phenotypic tolerance at high bacterial densities, and adaptive bacterial resistance in response to an aminoglycoside (tobramycin) against three Pseudomonas aeruginosa strains. At low-intermediate tobramycin concentrations (<4 mg/liter), bacterial killing due to the effect on protein synthesis was most important, whereas disruption of the outer membrane was the predominant killing mechanism at higher tobramycin concentrations (≥8 mg/liter). The extent of killing was comparable across all inocula; however, the rate of bacterial killing and growth was substantially lower at the 10(8.9) CFU/ml inoculum than that at the lower inocula. At 1 to 4 mg/liter tobramycin for strain PAO1-RH, there was a 0.5- to 6-h lag time of killing that was modeled via the time to synthesize hypothetical lethal protein(s). Disruption of the outer bacterial membrane by tobramycin may be critical to enhance the target site penetration of antibiotics used in synergistic combinations with aminoglycosides and thereby combat multidrug-resistant bacteria. The two mechanisms of aminoglycoside action and the new quantitative model hold great promise to rationally design novel, synergistic aminoglycoside combination dosage regimens