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

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

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

Conjugation of 10 kDa Linear PEG onto Trastuzumab Fab′ Is Sufficient to Significantly Enhance Lymphatic Exposure while Preserving in Vitro Biological Activity

The lymphatic system is a major conduit by which many diseases spread and proliferate. There is therefore increasing interest in promoting better lymphatic drug targeting. Further, antibody fragments such as Fabs have several advantages over full length monoclonal antibodies but are subject to rapid plasma clearance, which can limit the lymphatic exposure and activity of Fabs against lymph-resident diseases. This study therefore explored ideal PEGylation strategies to maximize biological activity and lymphatic exposure using trastuzumab Fab′ as a model. Specifically, the Fab′ was conjugated with single linear 10 or 40 kDa PEG chains at the hinge region. PEGylation led to a 3–4-fold reduction in binding affinity to HER2, but antiproliferative activity against HER2-expressing BT474 cells was preserved. Lymphatic pharmacokinetics were then examined in thoracic lymph duct cannulated rats after intravenous and subcutaneous dosing at 2 mg/kg, and the data were evaluated via population pharmacokinetic modeling. The Fab′ displayed limited lymphatic exposure, but conjugation of 10 kDa PEG improved exposure by approximately 11- and 5-fold after intravenous (15% dose collected in thoracic lymph over 30 h) and subcutaneous (9%) administration, respectively. Increasing the molecular weight of the PEG to 40 kDa, however, had no significant impact on lymphatic exposure after intravenous (14%) administration and only doubled lymphatic exposure after subcutaneous administration (18%) when compared to 10 kDa PEG-Fab′. The data therefore suggests that minimal PEGylation has the potential to enhance the exposure and activity of Fab′s against lymph-resident diseases, while no significant benefit is achieved with very large PEGs