Antimicrobial therapeutic plasma monitoring by applying PK/PD in burn patients

C. Sanches-Giraud1,2, D.S. Gomez3 and S.R.C.J. Santos1 1 School of Pharmaceutical Sciences, University of Sao Paulo - Sao Paulo/SP, Brazil. 2 Universidade Federal de São João del Rei, Campus Centro Oeste – Divinópolis, MG, Brazil. 3 Plastic Surgery and Burns Division, Hospital das Clinicas/Medical School, University of Sao Paulo - Sao Paulo/SP,

Brazil.

The aim of this chapter is to evaluate the contribution of antimicrobial therapeutic drug monitoring (TDM) to adjust dosing regimens in achieving control of infections using pharmacokinetics (PK) and pharmacodynamics (PD) to define the antimicrobial exposures that are necessary to maximise bactericidal activity and to inhibit bacterial growth. Robustness data exist for some antimicrobial agents, including the ratios of PK/PD parameters to the minimal inhibitory concentrations of bacteria that are associated with maximal antimicrobial effects (e.g., peak drug plasma concentration, Css

max:MIC ratio; area under the curve, AUCss0-24:MIC ratio; and time interval required to maintain the minimum plasma

drug concentration above the minimum inhibitory concentration, ΔT>MIC). The application of PK/PD tools for the effective control of severe infections must be considered for systemically administered antimicrobial agents that are prescribed to burn patients and other critically ill patients in the intensive care unit.

Keywords PK/PD correlation; therapeutic drug monitoring; antimicrobial; burn patients

1. Introduction

Burn-related injuries are the main causes of morbidity and mortality in burn patients, and remain among the three main causes of injury-related deaths. Disruption of the normal skin barrier, burn eschar, prolonged hospitalisation, immunocompromised status and broad spectrum antimicrobial therapy all make burn patients easy targets for microbial and fungal colonisation. Therefore, appropriate antimicrobial therapy has proven to be a major prognostic factor in patients who meet the clinical and laboratorial criteria for sepsis [1-3]. Thermal injuries negatively affect the pharmacokinetics of antimicrobial agents. In addition, high variability has been registered in this population of critically ill patients, making it difficult to establish dose regimen guidelines, and highlighting the importance of drug monitoring [4]. During a conventional dose regimen of an antimicrobial, e.g. vancomycin, a glycopeptide derivative that is largely prescribed to critically ill patients with severe infections such as sepsis, the trough concentrations are the basis for the physician’s intervention and subsequent dosage adjustments. A recent report indicated that higher doses of vancomycin were required to attain 10-20 μg/mL trough target concentrations in critically ill patients with sepsis [5]. In addition, studies evaluating empiric dosage recommendations for antimicrobials that are systemically administered to critically ill patients with nosocomial infections, and dose adjustments that were made following therapeutic plasma drug monitoring, pharmacokinetic data and PK/PD correlations, in burn patients are lacking [6]. Antimicrobial plasma levels that are lower than those that are required for the control of severe infections have been reported to result in pharmacotherapeutic failure, and may also contribute to the development of microbial resistance to anti-infective agents [7]. Significant changes in the pharmacokinetics of antimicrobial agents are expected to occur in critically ill patients, patients undergoing physiopathological stress, patients in the hyperdynamic phase, or patients who are suffering from sepsis. In addition, increases in the apparent volume of distribution have been associated with changes in the biological half-lives of these patients [8]. Cardiovascular, renal and hepatic functions have been previously reported to be altered as a result of thermal injuries. Consequently, after the systemic administration of antimicrobial agents, profound changes in pharmacokinetics occur in severe burn patients [2]. The empiric recommended initial dose regimen of antimicrobials is determined based on the characteristics of the critically ill burn patient, including age, renal function (such as renal impairment or end stage renal failure), cardiac output, and blood perfusion. However, changes in blood perfusion or routes of elimination can affect drug distribution, drug elimination and drug response as well. If the patient's physiological condition changes as a consequence of pathological events, antimicrobial dose adjustments will be required to achieve target concentrations of the drug. The optimal desired outcome can be obtained by applying the pharmacokinetic-pharmacodynamic (PK/PD) correlation for antimicrobial agents to guarantee control of severe infections in critically ill burn patients. Clinical benefits have been demonstrated over the past few decades for aminoglycoside agents using a systematic TDM programme for antimicrobial dose adjustment. Effective control of severe infections was obtained in these patients by applying PK/PD tools. These tools should also be applied to other systemically administered antimicrobial agents that are prescribed to burn patients in the intensive care unit [5, 9]. Therefore, the aim of this chapter is to discuss the application of pharmacokinetics (PK) and the pharmacokinetic/pharmacodynamic (PK/PD) correlation for dose

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adjustment requirements and their use to maximise drug efficacy and also to minimise the drug adverse effects in burn patients with severe nosocomial infections.

2. Antimicrobial pharmacokinetic changes in critically ill burn patients

Unpredictable pharmacokinetics was reported for burn patients in the intensive care unit (ICU) as a consequence of drug distribution. In addition, drug elimination was altered by physiopathological changes that occurred after thermal injuries, as illustrated in Figure 1 [10-13].

Fig. 1 Pharmacokinetic consequences of physiopathological changes in burn patients [10-13].

The inclusion of a new tissue fluid compartment under the eschar is necessary as a result of the vasodilation, microvascular permeability, and increases in extravascular pressure and osmotic pressure that occur after thermal injuries. The composition of the fluid under the eschar is quite similar to the composition of the plasma, including the levels of drugs contained within. If surgical procedures result in the elimination of the drug from the body, therapeutic failure will occur as a result of decreases in drug plasma and tissue concentrations. If the infection cannot be controlled during the antimicrobial therapy of a patient in the ICU, the eminent risk of developing microbial resistance against antimicrobial agents increases during the clinical course [13]. Consequently, the recommended empiric dose regimens that are reported in the literature are not applicable to critically ill burn patients. In addition, large intra-individual and interindividual variabilities in the pharmacokinetics of antimicrobial agents during the clinical courses of burn patients in the ICU have been reported. Intervention of the physician as soon as possible to adjust the dose based on the use of PK/PD tools would be feasible for the control of severe nosocomial infections in these patients [7, 10- 13], as described in Table 1.

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Table 1 Pharmacokinetic variabilities of antimicrobial agents in burn patients [7, 10- 13].

Intra-individual Variability Duration of time after the thermal accident Surgical procedures required Volemic maintenance after volume losses

Interindividual Variability Total burn surface area Age Past medical history and related co-morbidities Volemic maintenance after volume losses Creatinine clearance Serum albumin and α1- acid glycoprotein levels Sepsis

3. Antimicrobial plasma monitoring and clinical pharmacokinetics

The American Society of Health System Pharmacists (ASHP) defines clinical pharmacokinetics as a process that is used to determine the dosing schedule of an antimicrobial drug for an individual patient by applying pharmacokinetic principles in an effort to reach the target dose by maximisation of the pharmacotherapeutic effects of the drug and by minimisation of the toxicity related to severe adverse drug events. A series of advantages related to reductions in morbidity and mortality, reductions in the duration of antimicrobial therapy and the required length of hospitalisation, as well as significant reductions in adverse events related to drug toxicity were reported [14-17]. The application of pharmacokinetic principles requires an understanding of the characteristics of all of the mechanisms required for drug absorption, drug distribution, and the main routes of drug elimination by metabolism and/or excretion, while also taking in to account the disease and patient population. In addition, a series of factors must be considered, including age, gender, genetics, food/nutrition, physiological conditions and drug-drug interactions [15-18]. The Clinical Pharmacokinetics Centre has supported pharmacotherapeutic dose adjustment based on drug plasma measurements that are used to guide the optimisation of drug therapy in critically ill patients in hospitals in Europe, Canada and the United States of America since the 1980s. Unfortunately, few hospitals in developing countries have similar centres. In contrast, 40% of hospitals in the United States and Canada have a Clinical Pharmacokinetics Centre that provides pharmacotherapeutic dose adjustments for inpatients based on drug plasma levels and PK studies. Many of these facilities have been in operation since the 1990s [19]. Once the rate of sepsis increases in developing countries in Latin America, the hospitals in all Latin American countries will need to establish a programme based on this model/prototype and set up a Clinical Pharmacokinetics Centre and Therapeutic Drug Monitoring (TDM) service for antimicrobial dose adjustments that are focused on the effective control of nosocomial infections. A Clinical Pharmacokinetics Centre - TDM service in Latin American countries would result from a series of academic agreements in which laboratory and intensive clinical care expertise would be involved. A model could be developed by the staff from the Clinical Pharmacokinetics Centres of public universities, e.g. a School of Pharmacy & Pharmaceutical Sciences or a Medical School, that which involved experts in all of these areas, including the clinical staff from the medical school and the central laboratory of the hospital. The transfer of knowledge related to antimicrobial plasma monitoring and the PK/PD correlation could first be established at the hospital at the public university, and could potentially be very useful for controlling severe infections in critically ill inpatients. To establish a Clinical Pharmacokinetics Centre-TDM service, a series of requirements must be met, and the strategies must be well planned. Appropriate and robust bioanalytical methods must always form the basis of an effective TDM service. In this chapter, the considerations that are relevant to the selection of these methods, and the principles underlying the major analytical techniques that are currently in use, will be reviewed by comparing immunoassay and chromatographic techniques. Today, selecting the most appropriate bioanalytical methods to use for several antimicrobial plasma measurements is not easy, and the choice will depend upon the availability and expertise of the staff, as well as the equipment available. Plasma measurements of aminoglycoside agents, such as cefazolin, ciprofloxacin and vancomycin, can be done in the central laboratories of hospitals using commercially available kits. Several factors can be considered by comparing both of these techniques, as described in table 2.

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Table 2 Comparison of liquid chromatographic and immunoassay (commercial kits) antimicrobial plasma measurements

Analytical Considerations Liquid Chromatography Immunoassay Applicability Wide Limited Specificity Yes, always Sometimes Selectivity Yes, always Sometimes Automated assay/transfer to data analysis

Yes Yes

Sample volume required 0.05- 0.20 mL 0.05- 0.20 mL Calibration curve Linear correlation

R2> 0.98 Linear equation Nonlinear correlation Sigmoidal equation

Sensitivity (LOD) High Limited Accuracy/bias High Defined in the commercial kit Precision/variability High Defined in the commercial kit Recovery (absolute) High Not mentioned in the

instructions Recovery (relative to IS) High Not mentioned in the

instructions Stability (short/long term) Acceptable (bias<15%;

<20% LOQ) Defined in the commercial kit

Freezing/thawing cycles Acceptable (bias<15%) Not mentioned in the instructions

Post-processing stability Acceptable (bias<15%; <20% LOQ)

Not mentioned in the instructions

Speed/real-time from blood collection to laboratory data in the terminal

Slow-medium (24 hours) Slow – fast (6 - 8 hours)

Equipment costs High High - low Reagent costs Low Medium - high Skills required Medium-high Low - medium Drug suitability/statistics Good Good

The basic requirements of bioanalytical methods are described in the Good Laboratory Practices (GLP) sections of the international guidelines for the development of clinical protocols and drug measurements, which are available on regulatory agencies’ websites. These guidelines state that drug measurements should be accurate, precise, and have enough sensitivity to guarantee antimicrobial plasma measurements at dosing intervals, even if therapeutic failure occurs as a consequence of the patient having drug plasma levels that are lower than the minimum effective concentration that is required for the control of infection. The major advantage of liquid chromatographic techniques is their flexibility and adaptability to wide ranges of compounds, mainly by the simultaneous analysis of several analytes with similar chemical structures and physicochemical characteristics. In addition, many of the analytical parameters of the bioanalytical methods that are related to the limits of confidence and stability studies weren’t described in the kits' instructions, as described in table 4. However, most antimicrobial agents can be separated and quantified by means of suitable chromatographic systems using ultraviolet and visible detectors (UV-VIS), fluorescence or diode array detectors, permitting drug plasma measurements at very low concentrations that have high accuracy and precision as a consequence of the sensitivity, specificity and flexibility of the assay, making chromatographic procedures the first choice for antimicrobial plasma monitoring if simultaneous analyses of similar analytes can be performed. Currently, a series of antimicrobial plasma purification procedures can be applied prior to chromatographic analyses to remove analytes from biological matrices, for liquid-liquid extractions in alkaline, neutral or acidic media, for the precipitation of plasmatic proteins, for solid phase extraction or for ultrafiltration procedures using molecular sieve devices. Any disadvantages can be considered to have been addressed by the automated chromatographic method, because its superiority was demonstrated in comparison to immunoassays, as described above. Finally, the procedures that are used to ensure that quality assessments have been conducted in drug assays generally do not differ from those used to assess other analytes in drug assays, such as the Heathcontrol Scheme (UK), the External Quality Assurance Scheme from the University of Wales (Cardiff), or those schemes used for aminoglycoside agents that were provided by Southmead Hospital (Bristol, UK), or by KKGT in the Netherlands, as well as similar schemes that have been provided in Canada or the USA by the College of American Pathologists. Antimicrobial TDM services for the control of severe infections in critically ill burn patients start with the clinician's choice of the antimicrobial agent and empiric or initial recommended dose of the prescription. Because the agent that is causing the infection has not yet been isolated, and consequently, the susceptibility of the microbial agent to the

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antimicrobial agent prescribed has not been determined, dose adjustments based on antimicrobial plasma levels, pharmacokinetics, and the PK/PD correlation may be required if undesired clinical outcomes occur after the initial dosing regimen. In spite of reduced initiatives, TSM services were previously reported to contribute to desired clinical outcomes by controlling severe infections, such as sepsis, in critical burn patients [14, 16]. Therefore, antimicrobial TDM can be justified as follows:

• Optimal correlations between effective antimicrobial plasma levels and control of severe infections in critical patients.

• High correlations between toxicity and high antimicrobial plasma levels in critically ill patients on the recommended dose regimens due to the instability of organic function in those patients.

• High day-to-day intra- and inter-patient variabilities in pharmacokinetics, even on the same dose regimen. • Unpredictable pharmacokinetics due to the dysfunction of several organs. • Antimicrobial targets must be reached and maintained during pharmacotherapy to avoid the development of

microbial resistance. • The PK/PD correlation requires the interaction of teams from the TDM service and microbiology laboratory

who recognise the importance of determining the susceptibility of infective agents to antimicrobials that are available in the hospital for the control of severe nosocomial infections.

• Success in avoiding microbial resistance and achieving control of nosocomial infections in critically ill patients is the consequence of positive interactions between the partners from all of the teams participating in the TDM service, including the central laboratory/microbiology and clinicians from the Intensive Care Unit of the hospital.

Interpretation of drug analyses, pharmacokinetics and the PK/PD correlation requires reference values for all parameters. Even if a relevant question has been formulated, an appropriate specimen has been taken and an accurate result has been obtained, the whole exercise is of no value unless the result is correctly interpreted and any necessary action is taken. Interpretation of drug concentrations requires knowledge of the pharmacokinetic and pharmacodynamic factors that were outlined earlier in this chapter, and may demand considerable expertise. Unfortunately, without effective education programmes, users of TDM services frequently interpret results simply by comparing them to the therapeutic range and then either doing nothing or attempting to bring the levels closer to the quoted range. Much harm can be done in this process, because clinicians and laboratory workers frequently forget that the aim of the TDM process is to ameliorate the patients’ symptoms rather than to achieve drug levels that fall within a particular range. As previously mentioned, the target range may act as a mirror that provides a distorted reflection of the pharmacodynamic effects of antimicrobial agents against the infectious agent in the host. The therapeutic range for the trough is related to the accumulation of most systemic antimicrobial agents that are widely prescribed to critically ill patients with severe nosocomial infections and is the synthesis of a concept for each antimicrobial agent in which ‘the minimum effective concentration is related to drug efficacy, while its maximum plasma level is related to a safe concentration’. Between these limits, the majority of critically ill patients should experience maximum therapeutic benefits at minimal risk of toxicity and undesirable side effects. However, this simple theory breaks down in a number of important respects, and the therapeutic range must always be considered as a broad guide to assist the physician in the interpretation of laboratory data, which should always be conducted in parallel to clinical outcome for an individual patient at each pharmacotherapeutic follow up. Consequently, there is no reason for antimicrobial plasma monitoring in a patient who has reached the desired outcome at the end of drug treatment, is clinically stable and is not displaying any symptoms of drug toxicity. The organisation of a TDM service will start with the selection of an area with laboratory facilities, and by calculating the area nearby in which specialists cam perform pharmacokinetic analyses and PK/PD correlations. The basic essentials for an effective TDM service are the availability of appropriate bioanalytical methods and specialist expertise and the ability to produce results within a clinically relevant time frame. The main techniques available and the analytical aspects of routine drug analysis were discussed previously. However, a discussion regarding specialist expertise and clinically relevant turnaround time is now required. An effective TDM service requires an experienced staff containing an analyst, pharmacist, clinical biochemist, and pharmacokineticist. Supervisors are also required to monitor all of the steps involved in antimicrobial assessments, from blood sample collection through the final data analysis and discussion of the results with the clinician. Experienced analysts with knowledge of bioanalytical method development and validation who understand the bases of the procedures involved and have the competence to advise their employees on how to maintain the analytical sensitivity and specificity of those methods during routine practice are required. Clinical biochemists and pharmacists will be well aware of the disadvantages of multiple request forms, and a compromise is often reached by reserving a section of the general request form specifically for antimicrobial TDM, PK and PK/PD information. In addition, it is important to ensure that the request forms are properly completed and that any requests which do not contain essential information are either refused or shelved until the information has been provided. Such proposals may sound obstructive or unnecessary, but they are an essential part of the work conducted by a TDM service and they ensure that the results will be applied appropriately. Requests with inadequate documentation have been reported to be ignored

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when the results are returned. In addition, it is essential that all of the staff members on the TDM service team facilitate solutions to problems and have free access to the advice of a specialist who understands pharmacokinetics and therapeutics. A clinical pharmacist, clinical pharmacokineticist, or clinical biochemist or clinician with appropriate specialist training should be considered, and the best results will be obtained when a team approach is used in which the pharmacist, clinical biochemist, chemist and medical staff all play a role. Once involved, the specialists on staff may act in various roles. The effective and successful manner of running a TDM service requires that all requests be discussed prior to initiation with a clinical pharmacist who can advise whether the blood sample request is required and the appropriate timing of sample collections,. Following antimicrobial plasma analyses, data obtained from the Microbiology Centre Laboratory should be discussed with an analyst, clinical biochemist, pharmacist and pharmacokineticists and appropriate the recommendations should be conveyed to the patient's clinician. If screening requests arrive in the laboratory and are performed by a technician, the objectives can be achieved at lower cost and the 24 hr availability of a specialist is not required. It is essential to this approach that the request form contains full information regarding the reasons for the analysis, dosage regimen, length of time on the therapy, the timing of specimen collection related to the last dose, other prescribed drugs and the clinical status of the patient on the day of blood sampling. If the reason for the analysis is considered to be inappropriate, the specialist laboratory staff can contact the clinician and suggest a course of action that will avoid any intervention after the drug analysis has been performed. Considering the turnaround time required for onsite patient testing, the first question that needs to be addressed is whether the result is required immediately, and therefore needs to be provided virtually at the bedside or wherever the patient is seen, or whether a delay of some hours, or even days, is acceptable, allowing referral of the test to a more centralised laboratory service that likely has more sophisticated analytical facilities and greater interpretative expertise. This practice could be of financial advantage to most health care systems. Providing an onsite patient service is often expensive both in terms of staff time and reagent costs because the need for a rapid result generally necessitates the use of more expensive immunoassay systems, although HPLC systems have been used in the past. When blood samples are collected for antimicrobial TDM, drug accumulation must have reached steady state levels. If successive doses of a drug are administered, the drug begins to accumulate in the body. With first-order elimination, the amount of drug eliminated per unit of time is proportional to the amount of drug in the body. Accumulation continues until the rate of elimination approaches the rate of administration, a point at which the rate of drug going into the body by dose administration is equivalent to the rate of drug leaving the body via elimination processes. As the rate of drug elimination increases and approaches that of drug administration, the maximum (peak) and minimum (trough) concentrations increase until equilibrium has been reached. After that point, there will be no additional drug accumulation; the maximum and minimum concentrations will remain constant with each subsequent dose of the drug (Figure 2).

Fig. 2 Relationship of multiple dose drug administration to the average plasma drug concentration at the steady state. Abbreviations and symbols: D: dose; τ: time dosing interval; Css

Max: maximum concentration at the steady state; Cssmin: minimum concentration at

the steady state.

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When this equilibrium has been reached, the maximum (and minimum) drug concentrations are the same for each additional dose administered (assuming that the same dose and dosing interval are used). When the maximum (and minimum) drug concentrations for successive doses are the same, the amount of drug eliminated over the dosing interval (rate out) equals the dose administered (rate in), and the condition of "steady state" is reached. Steady state will always be reached after repeated drug administration at the same dosing interval if the drug follows first-order elimination. However, the time required to reach steady state varies from drug to drug depending on the elimination rate constant. When a drug has a higher elimination rate constant (e.g. a shorter half-life), steady state is reached sooner than when a drug has a longer half-life. Steady state is the point at which the amount of drug administered over a dosing interval equals the amount of drug being eliminated over that same period and is dependent upon the elimination rate constant. Therefore, when the elimination rate is higher, a greater amount of drug is eliminated over a given time interval. It then takes a shorter amount of time for the amount of drug eliminated and the amount of drug administered to become equivalent (and, therefore, achieve steady state). If the half-life of a drug is known, the time to reach steady state can be determined. If repeated doses of a drug are given at a fixed interval, then in one half-life, the plasma concentrations will reach 50% of the administered doses, but after five half-lives of treatment, the drug plasma concentration will reach 95% of the steady state level. The plasma concentrations will increase progressively, after which point, the steady state will be reached after approximately four or five half-lives. The concentrations at steady state may be abbreviated as Css. For example, an antimicrobial agent with a 6 hour half-life in patients with normal renal function will achieve steady-state concentrations within 30 hours, while a beta-lactam derivative with a 4 hour half-life will achieve steady-state concentrations within 20 hours. At steady state, the amount of drug equivalent to one dose is eliminated over one dosing interval. This apparently faster elimination is the result of the accumulation of the drug in the body. The relationships of pharmacokinetic parameters after multiple dose drug administration to the average plasma drug concentration at the steady state are described in table 3. Table 3 Pharmacokinetic parameters after multiple doses at the steady state[20]

Parameter Symbol (unit) Equation

Infusion Rate k0 (mg/hour) Dose/ Tinfusion

Elimination Rate Constant kel (h-1) (LnC1-LnC2)/T2-T1

Biological Half-life t(1/2)β (h) 0.693/ kel

Area Under the Curve-steady State

AUCSSτ(mg.h/L)

Trapezoidal rule (integration point to point at time dosing interval)

Plasma Clearance CLT

(mL/min/kg) Dose/ AUCSSτ

Apparent Volume of Distribution Vd (L/kg) (Dose/AUCSSτ)/kel

The American Society of Health System Pharmacists (ASHP) defines clinical pharmacokinetics as a process that is used to determine the dosing schedule of an antimicrobial drug for an individual patient by applying pharmacokinetic principles to reach the target by maximising pharmacotherapeutic drug effects and minimising the toxicity related to severe adverse drug events. A series of advantages related to reductions in morbidity and mortality, reductions in the duration of pharmacotherapy and hospitalisation required, as well as a significant reduction in the number of adverse events related to drug toxicity were reported [14-17]. The PK/PD correlation for antimicrobial agents recommends the use of TDM not only for target achievement but also to maintain drug efficacy against the most common nosocomial pathogens. In addition, TDM minimises the potential drug toxicity. Benefits of the application of TDM to antimicrobial agents were reported for critically ill patients, including burn patients in the intensive care unit, whose present unpredictable pharmacokinetics are the consequence of the dysfunction of several organs [14]. A sample clinical intervention for dose adjustment requirements based on plasma drug monitoring and the PK/PD correlation is illustrated in figure 3.

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Fig. 3 Clinical intervention for dose adjustment requirements based on the PK/PD correlation; adapted from [18].

4. Assessment of the minimum inhibitory concentration (MIC) by testing the susceptibility of microbial pathogens to antimicrobial agents

Minimum inhibitory concentration (MIC) is determined by testing the susceptibility of a pathogen to antimicrobial agents and is an in vitro measurement of the pharmacodynamics, or drug effects, of the microbial agent. In the example, when the antimicrobial MIC increases from 1 to 2 mg/L, the recommended clinical intervention will be to adjust the dose to achieve the target by decreasing the dosing interval and maintaining the dose, or by increasing the dose and not changing the dosing interval. In fact, it is not always adequate to alter the drug plasma concentration and therapeutic range for all antimicrobials in the same manner used for vancomycin. The pharmacokinetic parameter that is considered to be the recommended PK/PD target to predict drug efficacy can depend on drug plasma concentration, time plus drug plasma concentration, or can depend on the time to maintain the plasma drug concentration above the MIC. Consequently, reductions in antimicrobial susceptibility for a pathogen must result in an immediate clinical intervention by adjusting the antimicrobial dose to reach the target and maintain drug efficacy and control the infection, as well as avoid the development of resistance of this pathogen to the antimicrobial agent [14, 21]. MIC determination from the sample collected from the patient (catheter, sounds, fluids and secretions) could be the best data for the determination of the PK/PD correlation and target achievement. However, this practice cannot be considered to be a routine practice in hospitals for dose adjustments because it is considered to be quite expensive. Knowledge of the epidemiologic profile of pathogen types from each nosocomial unit and the MIC data are quite important for computing the PK/PD correlation. When these alternatives are not an option, MIC data may be available on specific sites that contain international databases, such as the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the Clinical and Laboratory Standards Institute (CLSI) [22, 23].

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5. Application of the pharmacokinetic-pharmacodynamic correlation to antimicrobial agents

The PK/PD correlation that is illustrated in figure 4 was determined using data that were obtained in vivo and in vitro from PK modelling. The parameters were estimated from the drug plasma concentration versus time (C:T), and the data were obtained by testing the susceptibility, expressed as the minimum inhibitory concentration, for an antimicrobial agent to inhibit the visible growth of the organism, as detected by the unaided eye after 18–24 h of incubation [24].

Fig. 4 Physiopathological changes and factors related to pharmacokinetic and pharmacodynamic variabilities on the PK/PD correlation of antimicrobial agents. Recently, several PK/PD parameters were reported to be able to predict the efficacy of antimicrobial agents for critically ill patients from the intensive care units of hospitals [9, 14, 25]. Antimicrobial efficacy can be related to drug plasma concentration, to time plus drug plasma concentration, or to the time to maintain the plasma drug concentration above the minimum inhibitory concentration (MIC).

a) Antimicrobial Time Dependence – drug efficacy against the pathogen is related to the time after the dose that the plasma drug concentrations are maintained above the MIC (%T>MIC). This parameter is expressed as the percentage of time dosing interval (based on in vivo data), where the antimicrobial plasma concentrations are higher than the minimum inhibitory concentration required to kill the pathogen (based on in vitro data).

b) Antimicrobial Plasma Concentration Dependence – drug efficacy against the pathogen is related to the ratio (Css

max/MIC), where the maximum antimicrobial plasma concentration after the dose was reached (based on in vivo data) and the MIC, the minimum inhibitory concentration, required to kill the pathogen (based on in vitro data);

c) Antimicrobial Plasma Concentration and Time Dependence – drug efficacy against the pathogen is related to the ratio (AUCss

0-24/MIC), where (AUCss0-24) is the Area Under the Curve of plasma drug concentration

versus time (based on in vivo data), and the MIC, the minimum inhibitory concentration, required to kill the pathogen (in vitro data);

The PK/PD parameters were illustrated in Figure 5 after the steady state had been reached.

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Fig. 5 Antimicrobial plasma concentration versus time curve at steady state levels: PK/PD parameters. Abbreviations: %T>MIC: time to maintain plasma levels (based on in vivo data) above the MIC: minimum inhibitory concentration (based on in vitro data); Css

max /MIC: ratio of the maximum plasma concentration reached (based on in vivo data) and the MIC: minimum inhibitory concentration (based on in vitro data); AUCss

0-24/MIC: ratio, area under the plasma concentration vs. time curve (based on in vivo data) and the MIC: minimum inhibitory concentration (based on in vitro data).

Classic examples of antimicrobial PK/PD correlations are dependent upon time, plasma drug concentration, or plasma drug concentration versus time and are summarised in table 4. Table 4 PK/PD correlations as predictive indices of antimicrobial efficacy against the most common nosocomial pathogens [9, 14, 25].

Pharmacodynamics Time dependence Plasma level dependence

Plasma level and time dependence

PK/PD Parameter %ΔT>CIM Cssmax /CIM AUCss

0-24/CIM

Antimicrobialss

β-lactams Carbapenems Linezolid Erythromycin Clarithromycin Lincosamide

Fluoroquinolones Aminoglycosides Metronidazole Telitromicina Daptomycin

Fluoroquinolones Aminoglycosides Azithromycin Tetracycline Glycopeptides Tigecycline Linezolid

Abbreviations: %ΔT>MIC: time to maintain plasma levels (in vivo data) above the MIC: minimum inhibitory concentration (based on in vitro data); Css

max /MIC: ratio of maximum plasma concentration reached (based on in vivo data) and the MIC: minimum inhibitory concentration (in vitro data); AUCss

0-24/MIC: ratio of the area under the plasma concentration vs. time curve (based on in vivo data) and the MIC: minimum inhibitory concentration (based on in vitro data).

6. Conclusion

The PK/PD correlation is an important and effective tool that can be used to make dose adjustments to antimicrobial agents that are mainly used to treat critically ill burn patients, which are often necessary due to the large variabilities and unpredictable pharmacokinetics of these agents. Any investigations into the benefits of applying these tools to optimal clinical outcomes during the pharmacotherapeutic follow-up of burn patients in the ICU have not been reported.

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However, as reductions in bacterial susceptibility to available antimicrobial agents occur as a function of many factors that are related to the pharmacokinetic variabilities, dose adjustments based on the PK/PD correlation are suggested because potential benefits to critically ill patients may be obtained by applying these powerful tools. Significant reductions in direct and indirect hospital costs may occur as a result.

Acknowledgements The support by CAPES and FAPESP is gratefully acknowledged.

7. Appendix

Definitions

• MIC: Minimum inhibitory concentration is defined as the lowest concentration that completely inhibits the visible growth of the organism, as detected by the unaided eye after 18–24 h of incubation at 35 °C with a standard inoculum of approximately 5 × 105–5 × 106 colony-forming units per millilitre (CFU/mL).

• PK: Pharmacokinetics – the study of the time course of drug absorption, distribution, metabolism and excretion.

• PD: Pharmacodynamics – the relationship between drug concentration at the site of action and the resultant effect, including the time course and intensity of therapeutic and adverse effects.

• Css: Plasma concentration at steady state. • Tss: Time required to reach the steady state. • Trough: Minimum plasma concentration (Css

min or Csstrough ).

• Peak: Maximum plasma concentration (Cssmax or Css

peak). • Tmax: Time required to reach the steady state. • AUCss

T: Area under the plasma concentration at steady state versus time interval curve.

• CLT: Total drug clearance from the body. Describes the removal of the drug from a volume of plasma in a given amount of time (drug loss from the body).

• Vd: Volume of distribution. Indicates the extent of drug distribution and aids in the determination of dosage requirements.

• t(1/2)β: Half-life. The time necessary for the concentration of the drug in the plasma to decrease by half.

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