Increased rates of carbapenem-resistant strains of Acinetobacter baumannii have forced clinicians to rely upon last-line agents, such as the polymyxins, or empirical, unoptimized combination therapy. ...Therefore, the objectives of this study were: (a) to evaluate the in vitro pharmacodynamics of meropenem and polymyxin B (PMB) combinations against A. baumannii; (b) to utilize a mechanism-based mathematical model to quantify bacterial killing; and (c) to develop a genetic algorithm (GA) to define optimal dosing strategies for meropenem and PMB.
A. baumannii (N16870; MICmeropenem = 16 mg/L, MICPMB = 0.5 mg/L) was studied in the hollow-fibre infection model (initial inoculum 108 cfu/mL) over 14 days against meropenem and PMB combinations. A mechanism-based model of the data and population pharmacokinetics of each drug were used to develop a GA to define the optimal regimen parameters.
Monotherapies resulted in regrowth to ~1010 cfu/mL by 24 h, while combination regimens employing high-intensity PMB exposure achieved complete bacterial eradication (0 cfu/mL) by 336 h. The mechanism-based model demonstrated an SC50 (PMB concentration for 50% of maximum synergy on meropenem killing) of 0.0927 mg/L for PMB-susceptible subpopulations versus 3.40 mg/L for PMB-resistant subpopulations. The GA had a preference for meropenem regimens that improved the %T > MIC via longer infusion times and shorter dosing intervals. The GA predicted that treating 90% of simulated subjects harbouring a 108 cfu/mL starting inoculum to a point of 100 cfu/mL would require a regimen of meropenem 19.6 g/day 2 h prolonged infusion (2 hPI) q5h + PMB 5.17 mg/kg/day 2 hPI q6h (where the 0 h meropenem and PMB doses should be ‘loaded’ with 80.5% and 42.2% of the daily dose, respectively).
This study provides a methodology leveraging in vitro experimental data, a mathematical pharmacodynamic model, and population pharmacokinetics provide a possible avenue to optimize treatment regimens beyond the use of the ‘traditional’ indices of antibiotic action.
Critically ill patients with severe infections are at high risk of suboptimal antimicrobial dosing. The pharmacokinetics (PK) and pharmacodynamics (PD) of antimicrobials in these patients differ ...significantly from the patient groups from whose data the conventional dosing regimens were developed. Use of such regimens often results in inadequate antimicrobial concentrations at the site of infection and is associated with poor patient outcomes. In this article, we describe the potential of in vitro and in vivo infection models, clinical pharmacokinetic data and pharmacokinetic/pharmacodynamic models to guide the design of more effective antimicrobial dosing regimens. Individualised dosing, based on population PK models and patient factors (e.g. renal function and weight) known to influence antimicrobial PK, increases the probability of achieving therapeutic drug exposures while at the same time avoiding toxic concentrations. When therapeutic drug monitoring (TDM) is applied, early dose adaptation to the needs of the individual patient is possible. TDM is likely to be of particular importance for infected critically ill patients, where profound PK changes are present and prompt appropriate antibiotic therapy is crucial. In the light of the continued high mortality rates in critically ill patients with severe infections, a paradigm shift to refined dosing strategies for antimicrobials is warranted to enhance the probability of achieving drug concentrations that increase the likelihood of clinical success.
Optimal combination therapy for Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae (KPC-Kp) is unknown. The present study sought to characterize the pharmacodynamics (PD) of polymyxin ...B (PMB), meropenem (MEM) and rifampin (RIF) alone and in combination using a hollow fibre infection model (HFIM) coupled with mechanism-based modelling (MBM).
A 10-day HFIM was utilized to simulate human pharmacokinetics (PK) of various PMB, MEM and RIF dosing regimens against a clinical KPC-Kp isolate, with total and resistant subpopulations quantified to capture PD response. A MBM was developed to characterize bacterial subpopulations and synergy between agents. Simulations using the MBM and published population PK models were employed to forecast the bacterial time course and the extent of its variability in infected patients for three-drug regimens.
In the HFIM, a PMB single-dose (‘burst’) regimen of 5.53 mg/kg combined with MEM 8 g using a 3-hr prolonged infusion every 8 hr and RIF 600 mg every 24 hr resulted in bacterial counts below the quantitative limit within 24 hr and remained undetectable throughout the 10-day experiment. The final MBM consisted of two bacterial subpopulations of differing PMB and MEM joint susceptibility and the ability to form a non-replicating, tolerant subpopulation. Synergistic interactions between PMB, MEM and RIF were well quantified, with the MBM providing adequate capture of the observed data.
An in vitro–in silico approach answers questions related to PD optimization as well as overall feasibility of combination therapy against KPC-Kp, offering crucial insights in the absence of clinical trials.
Abstract Background Changes in mean perfusion pressure (MPP) from premorbid resting values may contribute to the progression of septic acute kidney injury (AKI). Objectives In patients with septic ...shock, we aimed to investigate the association of changes from premorbid values with AKI severity and progression. Methods We obtained premorbid resting mean arterial pressure (MAP), central venous pressure (CVP), and MPP, and then recorded data from intensive care unit admission 2 hourly for the first 24 hours to calculate hemodynamic deficits. We recorded 4-hourly creatinine measurements for 96 hours. The association of hemodynamic variables with progression of AKI by Kidney Disease: Improving Global Outcomes ≥ 2 stages was explored by multivariate logistic regression. Results Of 107 patients, 55 (51.4%) had severe AKI. Median MAP deficit was similar for patients with or without severe AKI. Median MPP deficit was 29% in patients with severe AKI and 24% in those without ( P = .04), a difference determined by greater CVP levels. Central venous pressure was independently associated with worsening AKI (odds ratio, 1.26 95% confidence interval, 1.01-1.58; P = .04). Conclusions Mean arterial pressure and MPP deficits were substantial in septic shock patients, with patients with severe AKI having a greater MPP deficit. However, only CVP was independently associated with AKI progression. These findings suggest a possible role for venous congestion in septic AKI.
Very different labelling conventions are employed by different products of colistimethate (CMS), an inactive prodrug of colistin that is used as a last-line defence against Gram-negative 'superbugs'. ...This study examined the chemical composition and pharmacokinetics in rats of four commercial parenteral products of CMS.
Contents per vial of four brands of CMS from three different continents were weighed (n = 3). Elemental analysis and HPLC examination were conducted. The pharmacokinetics of CMS and formed colistin were investigated for each product after intravenous administration in rats (28.1 mg/kg CMS; n = 4). Blood was collected over 180 min, and concentrations of CMS and colistin were measured followed by pharmacokinetic analysis.
X-GEN, Paddock and Atlantic products, labelled with 150 mg 'colistin base activity', contained 366.8 ± 0.80, 340.6 ± 0.08 and 380.0 ± 5.97 mg CMS (sodium) per vial, respectively; while the Forest product (labelled with 2 000 000 IU) contained 159.3 ± 1.75 mg CMS (sodium). The elemental compositions of the four products were similar; however, the HPLC profile of the Atlantic CMS was different from those of the other three products. The pharmacokinetics of CMS were generally comparable across brands; however, the molar ratios (%) of the AUC0-180min of colistin to CMS (1.68% ± 0.35% to 3.29% ± 0.43%) were significantly different (P = 0.0157).
This is the first study to demonstrate that although different brands of CMS from various parts of the world have similar elemental compositions, they lead to different exposures to the microbiologically active formed colistin. The study has significant implications for the interpretation of pharmacological studies of CMS conducted in different parts of the world.
Linezolid is an oxazolidinone antibacterial agent indicated for serious gram‐positive infections. Only minor adverse effects were seen in phase III trials. However, more serious adverse effects were ...reported after commercial release, including cases of lactic acidosis, peripheral and optic neuropathy, and serotonin syndrome. Peripheral and optic neuropathy was usually seen after several months of linezolid therapy (median 5 mo), lactic acidosis after several weeks (median 6 wks), and serotonin syndrome after several days (median 4 days). Death occurred in two of seven reported cases of lactic acidosis, and three of 15 reported cases of serotonin syndrome. Improvement or complete recovery occurred in all cases of optic neuropathy, whereas complete recovery failed to occur in any patient with peripheral neuropathy. Linezolid should be discontinued immediately in patients experiencing these adverse effects. Patients receiving linezolid for more than 28 days should be monitored for signs of peripheral and optic neuropathy.
For fluoroquinolones, the area under the free plasma concentration-time curve divided by the MIC (fAUC/MIC) best predicts bacterial killing in mice and outcomes in patients. However, it is unknown ...whether the shape of the antibiotic concentration profile affects resistance emergence. Our objective was to compare killing and resistance between ciprofloxacin concentration profiles with different shapes at the same fAUC/MIC and identify the durations of ciprofloxacin exposure that minimize resistance emergence.
Static time-kill studies over 24 h using Pseudomonas aeruginosa ATCC 27853 assessed fAUC/MIC of 44 and 132 of ciprofloxacin (MICCIP = 0.25 mg/L) and fAUC/MIC of 22, 44 and 132 of ciprofloxacin plus an efflux pump inhibitor (MICCIP+EPI = 0.031 mg/L) at initial inocula of 10(4), 10(5) and 10(6) cfu/mL. Ciprofloxacin was added at 0 h and rapidly removed at 1, 4, 10, 16 or 24 h. Mutant frequencies and MICs were determined at 24 h.
High ciprofloxacin concentrations over 1-10 h yielded more rapid and extensive initial killing compared with 16 and 24 h exposures at the same fAUC/MIC. No resistance emerged for 1-10 h exposures, although regrowth of susceptible bacteria was extensive. Ciprofloxacin exposure over 24 h yielded less regrowth, but ciprofloxacin-resistant bacteria at 5× MIC amplified by over 5 log10 and almost completely replaced the susceptible bacteria by 24 h; MICs increased 4- to 8-fold. Resistance also emerged on 3× MIC, but not 5× MIC, plates when efflux was inhibited.
Pre-existing resistant subpopulations amplified extensively with 24 and 16 h exposures, but not with shorter durations. The shape of the ciprofloxacin concentration profile was critical to minimize resistance emergence.
Vancomycin-resistant enterococci (VRE) have emerged as an important nosocomial pathogen in medical centres worldwide. This study evaluated the impact of front-loading of linezolid on bacterial ...killing and suppression of resistance against VRE strains with defined genetic mutations.
Time-killing experiments over 48 h assessed the concentration effect relationship of linezolid against eight strains of vancomycin-resistant Enterococcus faecalis. A hollow fibre infection model (HFIM) simulated traditional and front-loaded human therapeutic linezolid regimens against VRE strains at 10(6) cfu/mL over 240 h. Translational modelling was performed using S-ADAPT and NONMEM.
Over 48 h in time-kill experiments, linezolid displayed bacteriostatic activity with >2 log(10) cfu/mL killing for all strains with an MIC of 4 and minimal activity against VRE with MICs of 16 and 64 mg/L. Against one strain with no resistant alleles (MIC 4 mg/L), 600 mg of linezolid every 12 h achieved maximal reductions of 0.96 log(10) cfu/mL over 240 h in the HFIM, whereas front-loaded 1200 mg of linezolid every 12 h ×10 doses or 2400 mg of linezolid every 12 h ×10 doses followed by 600 mg of linezolid every 12 h provided significantly improved killing with maximal reductions of 3.02 and 3.46 log(10) cfu/mL. Front-loaded regimens suppressed amplification of resistant subpopulations against VRE strains with no resistant alleles (MIC 4 mg/L) and postponed regrowth of resistant subpopulations against a VRE with 3.2 resistant alleles (MIC 4 mg/L). Modelling yielded excellent population fits (r = 0.934) and identified the number of sensitive alleles as a critical covariate.
Early, high-dose regimens of linezolid provided promising killing against selected susceptible strains and may be clinically beneficial if early bactericidal activity is necessary.
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