Papers by Michael Nikolaou
PLOS Computational Biology, Jan 6, 2011
Pharmacodynamic modeling has been increasingly used as a decision support tool to guide dosing re... more Pharmacodynamic modeling has been increasingly used as a decision support tool to guide dosing regimen selection, both in the drug development and clinical settings. Killing by antimicrobial agents has been traditionally classified categorically as concentration-dependent (which would favor less fractionating regimens) or time-dependent (for which more frequent dosing is preferred). While intuitive and useful to explain empiric data, a more informative approach is necessary to provide a robust assessment of pharmacodynamic profiles in situations other than the extremes of the spectrum (e.g., agents which exhibit partial concentration-dependent killing). A quantitative approach to describe the interaction of an antimicrobial agent and a pathogen is proposed to fill this unmet need. A hypothetic antimicrobial agent with linear pharmacokinetics is used for illustrative purposes. A non-linear functional form (sigmoid Emax) of killing consisted of 3 parameters is used. Using different parameter values in conjunction with the relative growth rate of the pathogen and antimicrobial agent concentration ranges, various conventional pharmacodynamic surrogate indices (e.g., AUC/MIC, Cmax/MIC, %T.MIC) could be satisfactorily linked to outcomes. In addition, the dosing intensity represented by the average kill rate of a dosing regimen can be derived, which could be used for quantitative comparison. The relevance of our approach is further supported by experimental data from our previous investigations using a variety of gram-negative bacteria and antimicrobial agents (moxifloxacin, levofloxacin, gentamicin, amikacin and meropenem). The pharmacodynamic profiles of a wide range of antimicrobial agents can be assessed by a more flexible computational tool to support dosing selection.
Journal of Antimicrobial Chemotherapy, Sep 19, 2005
Antimicrobial Agents and Chemotherapy, Nov 1, 2010
Killing by beta-lactams is well known to be reduced against a dense bacterial population, commonl... more Killing by beta-lactams is well known to be reduced against a dense bacterial population, commonly known as the inoculum effect. However, the underlying mechanism of this phenomenon is not well understood. We proposed a semimechanistic mathematical model to account for the reduced in vitro killing observed. Time-kill studies were performed with 4 baseline inocula (ranging from approximately 1 ؋ 10 5 to 1 ؋ 10 8 CFU/ml) of Escherichia coli ATCC 25922 (MIC, 2 mg/liter). Constant but escalating piperacillin concentrations used ranged from 0.25؋ to 256؋ MIC. Serial samples were taken over 24 h to quantify viable bacterial burden, and all the killing profiles were mathematically modeled. The inoculum effect was attributed to a reduction of effective drug concentration available for bacterial killing, which was expressed as a function of the baseline inoculum. Biomasses associated with different inocula were examined using a colorimetric method. Despite identical drug-pathogen combinations, the baseline inoculum had a significant impact on bacterial killing. Our proposed mathematical model was unbiased and reasonable in capturing all 28 killing profiles collectively (r 2 ؍ 0.88). Biomass was found to be significantly more after 24 h with a baseline inoculum of 1 ؋ 10 8 CFU/ml, compared to one where the initial inoculum was 1 ؋ 10 5 CFU/ml (P ؍ 0.002). Our results corroborated previous observations that in vitro killing by piperacillin was significantly reduced against a dense bacterial inoculum. This phenomenon can be reasonably captured by our proposed mathematical model, and it may improve prediction of bacterial response to various drug exposures in future investigations.
Antimicrobial Agents and Chemotherapy, Nov 1, 2008
To facilitate optimal dosing regimen design, we previously developed a mathematical model using t... more To facilitate optimal dosing regimen design, we previously developed a mathematical model using time-kill study data to predict the responses of Pseudomonas aeruginosa to various pharmacokinetic profiles of meropenem and levofloxacin. In this study, we extended the model to predict the activities of gentamicin and amikacin exposures against P. aeruginosa and Acinetobacter baumannii, respectively. The input data were from a time-kill study with 10 7 CFU/ml of bacteria at baseline. P. aeruginosa ATCC 27853 was exposed to gentamicin (0 to 16؋ MIC; MIC ؍ 2 mg/liter), and A. baumannii ATCC BAA 747 was exposed to amikacin (0 to 32؋ MIC; MIC ؍ 4 mg/liter) for 24 h. Using the estimates of the best-fit model parameters, bacterial responses to various fluctuating aminoglycoside exposures (half-life, 2.5 h) over 72 h were predicted via computer simulation. The computer simulations were subsequently validated using an in vitro hollow-fiber infection model with similar aminoglycoside exposures. A significant initial reduction in the bacterial burden was predicted for all gentamicin exposures examined. However, regrowth over time due to resistance emergence was predicted for regimens with a maximum concentration of the drug (C max)/MIC (dosing frequency) of 4 (every 8 h [q8h]), 12 (q24h), and 36 (q24h). Sustained suppression of bacterial populations was forecast with a C max /MIC of 30 (q12h). Similarly, regrowth and suppression of A. baumannii were predicted and experimentally verified with a three-dimensional response surface. The mathematical model was reasonable in predicting extended bacterial responses to various aminoglycoside exposures qualitatively, based on limited input data. Our approach appears promising as a decision support tool for dosing regimen selection for antimicrobial agents.
Journal of Antimicrobial Chemotherapy, Jan 9, 2012
It has been proposed that antimicrobial resistance could be associated with a fitness cost in bac... more It has been proposed that antimicrobial resistance could be associated with a fitness cost in bacteria, which is often determined by competition experiments between isogenic strains (wild-type and mutant). However, this conventional approach is time consuming and labour intensive. An alternative method was developed to assess the fitness cost in drug-resistant bacteria. Methods: Time-growth studies were performed with approximately 1×10 5 cfu/mL of Acinetobacter baumannii or Pseudomonas aeruginosa at baseline. Serial samples were obtained to quantify the bacterial burden over 24 h. The growth rates (K g) of isogenic strains (antibiotic susceptible and resistant) were determined individually and used to predict their relative abundance in a co-culture over an extended period of time. The predicted difference between the two strains was subsequently validated by in vitro growth competition experiments. Results: The growth rates of A. baumannii were not significantly different in different strengths of growth medium. The difference in bacterial burden observed in competition studies was in general agreement with the predicted difference based on K g values, suggesting good predicting ability of the mathematical model. Conclusions: The proposed mathematical model was found to be reasonable in characterizing bacterial growth and predicting the fitness cost of resistance. This simple method appears robust in the assessment of fitness cost associated with drug resistance and warrants further investigations.
1993 American Control Conference
The purpose of this paper is to propose an answer to the title&#39;s question, and examine th... more The purpose of this paper is to propose an answer to the title&#39;s question, and examine the ramifications of the provided answer. Our proposition is to quantify the nonlinearity of a system by a carefully defined 2-norm, which results from a newly constructed inner product. We develop the pertinent theory which allows the easy computation of this norm for a
1993 American Control Conference, 1993
ABSTRACT
1991 American Control Conference, 1991
ABSTRACT
Journal of Antimicrobial Chemotherapy, 2020
ObjectivesReduced in vitro β-lactam activity against a dense bacterial population is well recogni... more ObjectivesReduced in vitro β-lactam activity against a dense bacterial population is well recognized. It is commonly attributed to the presence of β-lactamase(s) and it is unknown whether the inoculum effect could be diminished by a β-lactamase inhibitor. We evaluated different β-lactam/β-lactamase inhibitor combinations in suppressing a high inoculum of ESBL-producing bacteria.MethodsThree clinical isolates expressing representative ESBLs (CTX-M-15 and SHV-12) were examined. The impact of escalating β-lactamase inhibitor (tazobactam or avibactam) concentrations on β-lactam (piperacillin or ceftazidime) MIC reduction was characterized by an inhibitory sigmoid Emax model. The effect of various dosing regimens of β-lactam/β-lactamase inhibitor combinations was predicted using %T>MICi and selected exposures were experimentally validated in a hollow-fibre infection model over 120 h. The threshold exposure to suppress bacterial regrowth was identified using recursive partitioning.Resu...
Day 3 Wed, September 28, 2016, 2016
More than 90% of producing oil wells require some form of artificial lift for pumping production ... more More than 90% of producing oil wells require some form of artificial lift for pumping production fluids to the surface (Bates, Cosad et al. 2004). The electrical submersible pump (ESP) is widely used and is currently the fastest growing form of artificial-lift pumping technology. About 15 to 20 percent of almost one million wells worldwide produce oil with the help of ESPs (Breit and Ferrier 2008). ESPs are usually considered more efficient and reliable among all oilfield lift systems and enable recovery of hydrocarbon fluids from greater depths at higher temperatures while handling a range of viscosities, gas-liquid ratios, and solids production. Over the years, the most common concern of operators using ESPs in their assets has been high workover costs and inadequately low system run life (Vandevier 2010). It is often observed that ESP performance declines gradually and reaches the point of service interruption due to a number of factors such as high gas volumes, high temperature,...
SPE Journal, 2016
SummaryOver the past decade, multiple-fracture horizontal wells (MFHWs) have proved successful in... more SummaryOver the past decade, multiple-fracture horizontal wells (MFHWs) have proved successful in recovering oil and particularly gas from very-low-permeability reservoirs. For MFHW planning and design, it is important to be able to make decisions on several variables, such as number of wells, number of fractures per well, amount and type of proppant per fracture, fracture dimensions (length, width, and height), and possibly others. Standard practice for making such decisions is mostly empirical. However, empiricism may not be as successful for new cases that are significantly different from old ones. In such cases, what-if analysis is used by combining intuition with numerical simulators to assess the outcomes of possible decisions. Even though this approach may produce feasible results, it is unlikely that it leads to optimal decisions because of the complexity of the problem. Therefore, a systematic methodology is needed for MFHW planning and design that produces optimal solution...
It is well known that no linear controller with integral action can stabilize a plant for which t... more It is well known that no linear controller with integral action can stabilize a plant for which the sign of the steady-state gain may change sign. A nonlinear control scheme must be used, such as nonlinear model-based control or adaptive control. In this work, we focus on an instance of this problem, in which the sign of the steady-state gain may change as a result of large unmeasured external disturbances entering a process with input multiplicities. The study is motivated by a specific gaseous emissions treatment unit in a chemical plant. External disturbances include large changes in the flow rate of hydrogen feed, which itself is combusted, thus potentially changing the air-to-fuel ratio in the process from lean to rich or vice versa. The objective of this paper is to explain the idiosyncracies of the dynamic behavior of the controlled process, suggest potential control system design strategies, and demonstrate some results via computer simulations. In particular, we demonstrate...
ABSTRACT We provide a smooth introduction to reduced-rank analysis via singular-value decompositi... more ABSTRACT We provide a smooth introduction to reduced-rank analysis via singular-value decomposition, and show how it can be used to monitor images of etched silicon wafers. An industrial case study is discussed.
SPE Kuwait Oil and Gas Show and Conference, 2013
In the last decade, upstream oil industry faced an exponential increase of the use of real-time d... more In the last decade, upstream oil industry faced an exponential increase of the use of real-time data, which lead to numerous digital oilfield (DOF) implementations. These have demonstrated the value to drive operations efficiency, optimize production, and maximize hydrocarbon recovery with better, faster decisions while reducing health, environmental and safety risks. Since the appearance of computers and the internet, many enabling technologies entered the oil-patch. Over the years, various areas improved as a result of significant commercial, corporate and academic efforts. However, some specific concerns remain be the same as a decade ago: data, value proposition, work processes, people skills and other aspects of change management. This paper focuses on the best practices that have made DOF implementations successful and the hard lessons learned. Many DOF implementations failed to deliver the expected value because of poor practices and misconceptions. These are presented in fou...
Nonlinear Model Predictive Control, 2000
We demonstrate how to use wavelets for the reparametrization of second-order Volterra models in t... more We demonstrate how to use wavelets for the reparametrization of second-order Volterra models in terms of a substantially smaller number of coefficients. The resulting structure retains several of the advantages of the Volterra structure, while being parsimonious, thus making feasible the identification of Volterra models from experimental data. A simulation study on a polymerization reactor elucidates the proposed approach.
SPE Bergen One Day Seminar, 2014
Automatic control becomes increasingly important to assist drilling operations. Basically, the fi... more Automatic control becomes increasingly important to assist drilling operations. Basically, the first stage of designing an automatic control for a simple system is by selecting a variable to be manipulated and a variable to be controlled in the system. A drilling rig has a large number of variables. This makes the design of automatic control more complex due to the number of variables. Here, we discuss three ways of dealing with ‘multivariable control’ design and evaluate them by simulation studies. The first approach is by designing a control system to coordinate all different variables in a centralised way. The second approach is by dividing the system into subsystems, each of which has fewer variables. A control system can be designed independently for each subsystem provided that the interactions between different subsystems are small. The third one is combination between the first and the second approach. The three different approaches of design are compared for coordination of...
All Days, 2010
Managed pressure drilling (MPD) is emerging as a powerful technology for precise control of wellb... more Managed pressure drilling (MPD) is emerging as a powerful technology for precise control of wellbore pressure within tight bounds. MPD comes in a number of variants, each taking a different approach to controlling pressure by creating a closed, pressurize mud circulation system. While MPD offers unprecedented pressure control capabilities, it creates operational complexity that renders many standard work flows unsuitable for reliable operation. This is because MPD requires that several tools (pumps, chokes, valves, etc) must be coordinated simultaneously, a task at which humans may not be particularly effective. A solution to this problem is the use of enabling automation tools. Such tools would reliably integrate MPD-related activities using a multi-level hierarchy, allowing humans to concentrate on higher-level decisions, while leaving the reliable execution of lowerlevel decisions to automation. In this paper a multi-level control approach of an MPD operation will be presented. T...
J. Process Control, 2000
... LESSONS FROM AN APPLICATION TO A SNACK FOOD PROCESS GABE HAARSMA a and MICHAEL NIKOLAOU b,* .... more ... LESSONS FROM AN APPLICATION TO A SNACK FOOD PROCESS GABE HAARSMA a and MICHAEL NIKOLAOU b,* ... emerging area in the past decade that provides means of diagnosing control loop performance (see Harris et al. [1] and Qin [2] for reviews). ...
Journal of Process Control, 2013
ABSTRACT This paper presents an evaluation of various control methods to be used during drilling ... more ABSTRACT This paper presents an evaluation of various control methods to be used during drilling operations where an unexpected gas influx occurs. In the event of an unexpected gas influx the current industry procedure is to control the pressure in the well manually. The drilling industry term for this manual procedure is well control. The focus of the paper is threefold. Firstly, to design an automatic sequence which is similar to the existing manual procedure. Secondly, to evaluate three different control algorithms for pressure control during an unexpected gas influx, and thirdly, to evaluate control parameter tuning needed when implementing different control algorithms.The control methods have been evaluated on various drilling scenarios with unexpected gas influx, referred to as a kick. After a kick of reservoir gas has entered the well, automatic control of the well control choke and rig pump is applied to compensate for pressure fluctuations while circulating out the gas. A PI controller is designed to stabilize the well pressure by controlling the well control choke, an internal model controller (IMC) controls the pressure by manipulating the choke and the rig pump flowrate, and a model predictive controller (MPC) uses coordinated control of the choke and the pump flowrate to stabilize the well pressure. The model based controllers use a simple first order model of the well. Simulations are performed using a detailed flow model of the well to test the controller performance and robustness. Several cases with different amounts of gas influx are investigated.The simulations show that it is feasible to control the pressure using automatic control of the choke valve and pump during an unexpected gas influx by use of all the presented control methods. The control methods are robust against changes in process conditions and disturbances, as they are able to handle several pressure levels and gas volumes without requiring re-tuning. However, since the pressure dynamics in the well are influenced when gas is entering the well, the model based controllers could probably be further improved if the models were updated after the gas influx occurred.The results indicate that adaption of the automatic sequence to the current manual procedure is applicable. However, to avoid a reduction in downhole pressure when stopping the pump and shutting in the well, the automatic sequence may be further improved beyond what is feasible with manual operation.
Uploads
Papers by Michael Nikolaou