Pharmacokinetics and Pharmacodynamics of Antimicrobials in Critically Ill Patients

Abstract

Critically ill patients with severe infections often have altered pharmacokinetic and pharmacodynamic variables that lead to challenging treatment decisions. These altered variables can often lead to inadequate dosing and poor treatment outcomes. The pharmacokinetic parameters include absorption, distribution, metabolism, and excretion. Pharmacodynamics is the relationship between drug serum concentrations and pharmacologic and toxicologic properties of the medication. In addition to these altered parameters, these critically ill patients frequently are receiving organ support in the forms of continuous renal replacement therapy or extra-corporeal membrane oxygenation. Altered pharmacodynamics can lead to decreased end-organ perfusion, which can ultimately lead to treatment failure or exposure-related toxicity. The most common antimicrobials utilized in the intensive care unit are classified by the pharmacodynamic principles of time-dependent, concentration-dependent, and concentration dependent with time-dependence. Thus, the aim of this review is to outline pharmacokinetic and pharmacodynamic changes of critically ill patients with severe infections and provide strategies for optimal antibiotic agent dosing in these patients.

Critically ill patients with severe infections often face challenging treatment decisions and high death rates [1]. The pharmacokinetic parameters such as absorption, distribution, metabolism, and excretion are often altered in the critically ill patient population compared with non-critically ill patients. This can lead to inadequate dosing and poor treatment outcomes. This article will review these pharmacokinetic and pharmacodynamic principles in critically ill patients and how they affect certain antimicrobial classes.

Pharmacokinetics

Absorption

Absorption is the rate at which a medication leaves the site of administration and moves into circulation. In addition, bioavailability is the pharmacokinetic term used to describe the percentage of an administered dose of drug that reaches circulation. Further, the bioavailability of a drug administered intravenously is 100%. Absorption is required for various routes of administration, including enteral, inhalation, topical, subcutaneous, intramuscular, and rectal [2]. Bioavailability from subcutaneous, intramuscular, or enteral administration is affected by absorption and first-pass metabolism.

The two primary factors influencing bioavailability of enterally administered medications are the amount of drug absorbed and first-pass metabolism by the liver. Many drug-specific variables can influence drug absorption, including particle size, solubility, lipophilicity, ionization, and the dissociation rate constant of the drug. Factors influencing the gastrointestinal (GI) tract can also alter drug absorption, such as gastric pH, regional blood flow, surface area, and motility [2]. The focus of this section is on the influence of vasopressor use, altered gastric emptying, and motility.

Hypotension and shock are known to cause the shunting of blood toward vital organs and away from less vital organs. To our knowledge, no studies clearly demonstrate the effect of hypotension or shock on the enteral absorption of drugs. Thus, clinicians are left to extrapolate changes in splanchnic blood flow to the likelihood that GI absorption is altered. Re-distribution of blood away from the splanchnic circulation is thought to decrease drug absorption from the GI tract. The hyperdynamic phase of sepsis or septic shock can increase cardiac output. In addition, vasopressors may contribute to regional hypoperfusion, which could result in decreased absorption of drugs. In late sepsis, it is thought that splanchnic blood flow is decreased, but no studies have verified this. This uncertainty in splanchnic blood flow, GI absorption, and the variable effect of vasopressors leads many clinicians to forgo the enteral route for drug administration.

Volume of distribution

Volume of distribution (Vd) is one of the most important pharmacokinetic properties affecting antibiotic agent dosing in critically ill patients, and an inaccurate assessment of this property has the potential to lead to serious clinical consequences, both by over- and underdosing of antibiotic agents.

Antibiotic agents that distribute in the extracellular fluid (hydrophilic) have a low Vd, while those that have rapid cellular uptake (lipophilic) have a high Vd. Sepsis leads to the development of endothelial leakage, which causes an increase in capillary permeability. This capillary leak syndrome results in re-distribution of fluid into the extracellular compartment, which leads to an increase in Vd of hydrophilic drugs with a subsequent drop in their concentrations, leading to sub-therapeutic levels. This can be perpetuated further by volume resuscitation, the presence of mechanical ventilation, extra-corporeal circuits, or post-surgical drains. Patients with burns may also have an increased Vd of hydrophilic drugs (Table 1).

Table 1.

Sepsis-Induced Pharmacokinetic Changes

Capillary leak	Altered protein binding	Augmented renal clearance	End organ dysfunction
Increased Vd	Increased CL Increased Vd	Increased CL	Decreased CL
Low plasma concentration	Low plasma concentrations	Low plasma concentrations	High plasma concentrations

Vd = volume of distribution; CL = clearance.

Lipophilic drugs typically have a large Vd because of distribution into adipose tissue and, therefore, the increased Vd that results from capillary leak syndrome is likely to cause little subsequent change in drug Vd [3]. Higher doses of hydrophilic drugs than would be calculated from traditional equations may be needed in these patients to reach therapeutic peak concentrations. Further, population-based dosing nomograms that are sometimes used to calculate aminoglycoside doses, such as the Hartford Nomogram, may be inaccurate in this population [4].

Protein binding is a factor that may influence the Vd and clearance (CL) of many antibiotic agents. The pharmacokinetics for highly protein bound drugs are altered in sepsis and can result in higher unbound concentrations that are subject to greater clearance. Hypoalbuminemia is a common condition in patients with sepsis as a consequence of increased capillary permeability. There is an increased albumin escape through the leaky endothelium, which will result in loss of oncotic pressure and fluid into the interstitial space. This albumin escape is one factor that influences the Vd and CL of many antibiotic agents. The decrease in plasma albumin in critical illness leads to an increase in the free fraction of a drug that is ordinarily highly bound to this protein [4]. Unbound fractions of antibiotic agents are available not only for elimination, but also for distribution. Highly protein bound antibiotic agents that likely develop altered pharmacokinetics from hypoalbuminemia include oxacillin, ceftriaxone, ertapenem, and daptomycin [3,5]. In addition, uremia, low pH, and some other drugs may decrease serum protein binding further [6].

Metabolism

The predominant location for drug metabolism is the liver, but it can include tissues such as the GI tract, kidneys, lung, and brain. Hepatic drug metabolism can be classified broadly into phase 1 and phase 2 metabolism. Nearly all of phase 1 metabolism takes place in the hepatic cytochromes and undergoes a number of transformations including oxidation and methylation to make the parent drug more water soluble to facilitate renal excretion. Phase 1 metabolism is capacity limited, meaning the liver's capacity to metabolize drugs by phase 1 enzyme systems is compromised when in failure; however, the liver's metabolic capacity has to be reduced by >90% before drug metabolism is significantly affected. Phase 2 metabolism includes glucuronidation and glutathione conjugation. Phase 2 metabolism is less capacity limited and will occur even in end-stage liver failure [7]. There are little data available, however, to guide antibiotic dose adjustments in critically ill patients with liver dysfunction [5].

Excretion

Any reduction in renal perfusion, including microcirculatory failure, can lead to acute kidney injury (AKI) and reduced CL of renally eliminated antibiotic agents. Acute kidney injury is defined as any of the following: Increase in serum creatinine (Scr) by ≥0.3 mg/dL within 48 hours, increase in Scr to ≥1.5 times baseline, which is known or presumed to have occurred within the previous seven days, or urine volume <0.5 mL/kg/h for six hours [8]. For most drugs, the kidneys are the primary site for excretion of the parent drug, metabolites, or both. Urinary excretion of a drug is dependent on filtration, secretion, and re-absorption. Critically ill patients may experience increased, decreased, or normal renal excretion of drugs. The state of renal excretion depends on many factors and can change rapidly depending on how the clinical condition progresses. Critically ill patients can have a diagnosis of various stages of AKI, although in some of them, renal function still can remain intact. The frequency of AKI in critically ill patients is estimated to be 50%–65%, and while in one third of the cases, it occurs as a late complication, in approximately two thirds, it is being diagnosed within the first 24 hours after admission to the intensive care unit (ICU) [9,10].

It is crucial to understand that causes of AKI are not limited to alterations in the glomerular filtration rate (GFR), but also affect the process of tubular secretion and re-absorption. Sepsis-induced AKI is not only associated with decreased glomerular filtration, but also with impairment of tubular secretion and re-absorption [11]. This will result in decreased antibiotic clearance of hydrophilic antibiotic agents (aminoglycosides, glycopeptides, and beta-lactams), prolonged half-life and potential toxicity from elevated antibiotic plasma concentrations, and accumulation of metabolites. Antibiotic agents that undergo post-filtration re-absorption, such as fluconazole, have a CL that is increased in patients with AKI and anuria undergoing continuous renal replacement therapy (CRRT), necessitating an increase or even doubling of the amount of administered drug [12]. When AKI is present or the patient requires renal replacement therapy (RRT), there needs to be individualized therapy and dose adjustments made to reflect these changes.

Most antibiotic agents in critically ill patients are cleared renally and, therefore, their concentrations will be affected by changes in renal function. Although standard practice is to reduce antibiotic doses in the presence of AKI to avoid toxic effects, in some critically ill patients, augmented renal clearance can develop where glomerular filtration is increased. Augmented renal clearance refers to enhanced renal elimination of drug, and its diagnosis relies on GFR values (calculated on the basis of measurements of Scr that are 10% higher than normal or above 130 mL/min/1.73 m²) [13,14]. It is driven by the pathophysiologic responses to infection and treatment interventions (fluid resuscitation and use of vasopressors) that are also associated with an early increase in cardiac output and enhanced blood flow to major organs. Increased perfusion to the kidneys enhances drug delivery and, therefore, increases glomerular filtration and clearance of renally cleared solutes, leading to underdosing of antibiotic agents such as aminoglycosides, beta lactams, and glycopeptides [5].

Early recognition and diagnosis of this disorder can contribute to successful treatment by allowing clinicians to compensate for the enhanced elimination of antibiotic agents by the kidneys by increasing the dosage or shortening the dosing interval. Augmented renal clearance is commonly observed among critically ill patients who are younger men with trauma, sepsis, burns, or pancreatitis [5,14,15].

Organ support

Critically ill patients with severe renal dysfunction necessitating CRRT also have altered pharmacokinetics. The three main modalities of CRRT are continuous venovenous hemodialysis (CVVHD), continuous venovenous hemofiltration (CVVH), and continuous venovenous hemodiafiltration (CVVHDF). To administer proper doses to these patients, knowledge of the pharmacokinetic changes and clearances obtained by the specific type of CRRT is needed [16]. Drug properties affected by CRRT include molecular weight, protein binding, Vd, and drug charge [17]. CVVH removes solute by convection allowing larger molecules to be removed, while in CVVHD, drug clearance occurs by passive diffusion allowing a higher CL of smaller molecules with a low molecular weight. CVVHDF removes molecules by both diffusion and convection [18]. It has been recommended that the initial dose of antimicrobial agents be based on the published Vd and subsequent doses be based on an estimate of total CL or the sum of the residual renal clearance, non-renal non-CRRT clearance, and CRRT clearance [16,19,20]. It is also important to note that when patients transition to intermittent hemodialysis, the rate of solute removal will change, and dosing should be adjusted accordingly.

Patients who are critically ill with cardiac and/or respiratory failure may undergo extracorporeal membrane oxygenation (ECMO), which is a cardiopulmonary bypass device circuit used for temporary support. This lifesaving system causes alterations in antimicrobial pharmacokinetics that can lead to therapeutic failure and drug toxicity. Studies in pediatric patients have demonstrated that the ECMO circuit leads to sequestration of certain antibiotic agents that leads to a decreased amount reaching the body [21]. In addition to this sequestration, there is an increased Vd and decreased drug elimination, which can lead to suboptimal antimicrobial concentrations in the body [22,23]. These trends, however, have not been consistently observed in adult patients. The pharmacokinetic parameters vary based on the individual antibiotic agent, and it has been shown that for vancomycin, piperacillin-tazobactam, meropenem, and amikacin, there were no significant differences when patients were on ECMO. Further large pharmacokinetic studies are needed to provide optimal dosing guidelines for patients receiving antimicrobial agents on ECMO [24].

Pharmacodynamics

The relationship between drug serum concentrations and pharmacologic and toxicologic properties is termed pharmacodynamics. The main interest for antimicrobial agents is the relationship between drug concentration and the antimicrobial effect [25]. Successful antimicrobial therapy requires sufficient drug concentrations that kill or suppress bacterial growth at the site of infection. Critical illness can severely alter antimicrobial pharmacodynamics, such as decreased end-organ perfusion leading to treatment failure because of inadequate drug concentrations at the site of infection, or exposure-related toxicity [26].

To provide optimal doses of antimicrobial agents in critically ill patients, one must understand the exposure-effect relation of the drug and pathogen. There are three pharmacodynamic parameters that define this relationship: Time-dependent, concentration-dependent, and concentration dependent with time-dependence [27]. The pharmacodynamic parameters used to characterize antimicrobial activity of bacteria are the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC). Antimicrobial agents can be categorized by these pharmacodynamic parameters (Table 2).

Table 2.

Classification of Antimicrobial Agents according to Pharmacodynamic Principles

Pharmacodynamic variable	Antimicrobials
Time above MIC killing (fT>MIC)	Beta-lactams Macrolides Clindamycin Linezolid
Concentration dependent killing (Cmax/MIC)	Aminoglycosides
Concentration and time dependent killing (AUC/MIC)	Polymixins Fluoroquinolones Glycopeptides Daptomycin

MIC = minimum inhibitory concentration; fT>MIC = fraction of antibiotic above the MIC; Cmax = maximum concentration; AUC = area under the curve.

Maximal bacterial killing for time-dependent antimicrobial agents is based on the time the unbound fraction of antibiotic is above the MIC, known as fT>MIC [27]. The most widely recognized class of antimicrobial agents with time-dependent killing are the beta-lactam antibiotic agents. Other classes of antibiotic agents that demonstrate fT>MIC killing include the macrolides and clindamycin. Drug exposure can be affected by changes in Vd and increased drug CL in the critically ill. These antimicrobial agents should be dosed more frequently, rather than administered in higher doses, to optimize bacterial killing [25,27].

Antimicrobials that demonstrate concentration-dependent bacterial killing require a higher peak concentration over the MIC of the bacterial pathogen (Cmax/MIC). Therefore, higher doses lead to higher concentrations, which leads to a greater rate and extent of bactericidal activity rather than more frequent dosing. The aminoglycosides are the most common class of antimicrobials that exhibit this type of bactericidal killing. Maximal antibacterial killing with aminoglycosides is thought to occur when the Cmax/MIC is 8 to 10 times greater than the MIC [28,29]. In critically ill patients, it may be challenging to achieve these concentrations using standard dosing; therefore, higher daily doses may be required [30].

Concentration and time-dependent bacterial killing is the last pharmacodynamic variable. For these antibiotic agents, the area under the concentration-time curve during a 24-hour period to the MIC ratio (AUC/MIC) is used to guide dosing [27]. The fluoroquinolones and the glycopeptides are two classes of antimicrobial agents that exhibit this pharmacodynamic principle.

Antimicrobials

Time-dependent

Beta-lactam antibiotic agents bind with the penicillin-binding proteins and inhibit bacterial cell wall synthesis; and as a class, they exhibit wide spectra of activity against gram-positive bacteria, gram-negative bacteria, and anaerobes, which varies across each sub-class and agent [31]. Beta-lactams are time-dependent antibiotic agents, exerting their bacterial killing effects based on the time that fT>MIC; although the optimal fT>MIC varies, near maximal bactericidal effect is observed typically with a fT>MIC of 40%–70% for cephalosporins, 30%–50% for penicillins, and 20%–40% for carbapenems with concentrations 4 to 5 times the MIC required [32 –35]. In addition, beta-lactams are hydrophilic antibiotic agents, and in patients with sepsis who have received fluid resuscitation, lower serum antibiotic concentrations may be observed [32]. Because of this increased Vd, loading doses and larger maintenance doses are usually required to attain adequate pharmacodynamic concentrations. In addition, most beta-lactams (excluding ceftriaxone and oxacillin) are minimally protein bound and are renally excreted, necessitating adjustment in renal dysfunction [35].

It is also necessary to be aware of augmented renal clearance early in sepsis, in which case it would be essential to shorten the dosing interval to ensure adequate dosing [32]. Traditionally, beta-lactams have been administered via intermittent bolus dosing; however, because of their time-dependent characteristics, this dosing strategy has been questioned as to whether it is the most efficacious [33]. Continuous infusions have been demonstrated to provide higher blood concentrations with a greater fT>MIC compared with intermittent dosing [33]. The question still remains as to whether this increased fT>MIC leads to improved efficacy and decreased adverse effects, specifically in critically ill patients in septic shock [33,34].

Many trials investigating this question have several limitations, including a retrospective nature, non-equivalent dosing between continuous and intermittent bolus arms, and inclusion of a less critically ill population [32,33,36]. A prospective, multi-center, double-blind study evaluated 60 patients with severe sepsis who were receiving ticarcillin-clavulanate, piperacillin-tazobactam, or meropenem [33]. Patients were randomized to receive either an active infusion with placebo boluses or placebo infusion with active boluses. There was a statistical difference between the fT>MIC between the intervention and control group (81.8% vs. 28.6%, p = 0.001) and clinical cure (76.7% vs. 50%, p = 0.032), but no difference was found in ICU length of stay (7.5 [4 –12] vs. 9 [5–14.25], p = 0.5), ICU survival (93.3% vs. 86.7%, p = 0.67), and hospital survival (90% vs. 80%, p = 0.47), although the study was not powered to find a difference in clinical outcomes [33].

Linezolid inhibits bacterial protein synthesis and has activity against gram-positive organisms. It is bacteriostatic against enterococci and staphylococci and bactericidal against most strains of streptococci [37]. Linezolid is primarily a time-dependent antibiotic agent and demonstrates bacteriostatic efficacy with a fT>MIC of at least 40%, but ideally 85%–100% in severe infections necessitating bactericidal activity [38,39]. The AUC/MIC ratio also can be evaluated, targeting 80–120. Linezolid has standard dosing of 600 mg intravenous/oral (IV/PO) every 12 hours regardless of organ dysfunction or patient weight and achieves high tissue penetration, although IV should be used in patients who are at risk for decreased absorption because of pharmacokinetic changes [38].

A study that examined plasma and interstitial fluid concentrations of linezolid in several patient populations found that while linezolid achieved adequate tissue penetration in patients with sepsis, this patient population saw lower tissue exposure, which prompted the authors to recommend a loading dose on the first day of therapy; however, with this study being conducted in a small number of patients and evaluating only tissue concentrations rather than clinical outcomes, these recommendations may not be widely applicable [38].

In addition, linezolid clearance is composed of 35% renal excretion and 65% non-enzymatic oxidation [38]. It also demonstrates low plasma binding and a Vd similar to total body water (40–50 L) [38,40]. In critically ill patients with sepsis, increased Vd and CL may contribute to sub-optimal serum and tissue concentrations [39]. Because of this, continuous infusion linezolid has been proposed [39]. A study evaluating intermittent (600 mg IV every 12 h) versus continuous (300 mg IV loading dose and 900 mg continuous infusion on day 1 followed by continuous infusion of 1200 mg/daily) infusion linezolid found less fluctuations in serum levels, which were always above the susceptibility break point (4 mg/L) in patients receiving intermittent infusion. Continuous infusion also allowed for more patients to have fT>MIC to be greater than 85% (100% vs. 40%; p < 0.05), which led the authors to conclude that there is a theoretical benefit to providing a continuous infusion of linezolid, although further clinical studies are warranted [39].

Lincosamides, including clindamycin and lincomycin, reversibly inhibit bacterial protein synthesis and exhibit activity against some staphylococci and streptococci as well as anaerobes [41]. Clindamycin is lipophilic and has a Vd that is not affected by fluid resuscitation [3,42]. Lincosamides have high extra-renal clearance, which has been shown to be decreased in critically ill patients with sepsis [32,42,43]. Lincosamides are time-dependent antibiotic agents, and their efficacy is measured in fT>MIC, which should be at least 40%–50% and is usually achieved in critically ill patients [3,42].

Concentration-dependent

Aminoglycosides interfere with bacterial protein synthesis by binding to the 30S sub-unit, disrupting the bacterial membrane, and are active primarily against gram-negative bacteria with gram-positive synergistic activity [44]. Because early appropriate antibiotic therapy has been shown to improve mortality rates in patients in septic shock, aminoglycosides are sometimes added to broaden coverage to cover for possible multi-drug resistant gram-negative organisms [45,46]. Aminoglycosides are hydrophilic antibiotic agents that are affected by fluid resuscitation necessary for the management of sepsis and septic shock; therefore, loading doses are required to help achieve adequate plasma concentrations quickly [32,47]. Allou et al. observed that patients with a positive fluid balance were less likely to achieve adequate concentrations after receiving a single dose of gentamicin 8 mg/kg [47].

Aminoglycosides exhibit concentration-dependent antibiotic killing, and because their activity is exhibited in the peak effect, providing one large daily dose is clinically efficacious with decreased toxicity because of the post-antibiotic effect. This effect allows for bacterial killing even after the drug concentration at the site of infection drops below the MIC [32,35,45]. In a study of patients with severe sepsis or septic shock, a loading dose of amikacin 30 mg/kg was found to achieve adequate levels in 81.8% of patients, but did find supra-therapeutic levels in 40% of patients, which was associated with a higher probability of mortality [45]. In patients with renal failure, it may be necessary to prolong the dosing interval between 36–48 hours [32]. Therapeutic drug monitoring (TDM), utilizing peak and trough measurements, is recommended to allow for individualization in the changing clinical status, focusing on optimizing efficacy and minimizing adverse effects [48].

The Hartford Nomogram is not validated in critically ill patients and, therefore, patient-specific TDM is required [35]. Peak concentrations are monitored to ensure clinical efficacy by the ability to achieve adequate peak to MIC concentrations, and trough concentrations are monitored to determine clearance of the drug and prevent toxicity [32].

AUC/MIC

Polymyxin antibiotic agents such as colistin and polymyxin B, have been available since the 1960s, but fell out of favor because of increased toxicities, including nephrotoxicity and neurotoxicity [49]. They damage the bacterial cytoplasmic membrane causing leakage of intracellular substances and death, and with the emergence of multi-drug resistant gram-negative bacteria, these agents have been re-investigated as treatment options [49,50]. Colistin is thought to have predominantly concentration-dependent bacterial killing activity, but its pharmacodynamics effects are best characterized by looking at the AUC/MIC ratio [3,51]. Colistin is a hydrophilic antibiotic agent and, therefore, increased Vd from fluid resuscitation is likely to decrease tissue concentrations as well as peak concentrations [3,32]. Dosing is on the basis of weight as well as renal function. The optimal dosing strategy that capitalizes on adequate concentrations while reducing toxicity is still debated [3].

Vancomycin is a glycopeptide that inhibits bacterial cell wall synthesis and has gram-positive coverage, including methicillin-resistant Staphylococcus aureus (MRSA) [52]. Glycopeptides are hydrophilic antibiotic agents and, therefore, loading doses should be used in the setting of fluid resuscitation in patients with sepsis [32]. Although a more accurate measure of vancomycin efficacy is the AUC/MIC ratio with a goal of >400, clinically this method is not readily available at most institutions; therefore, C_minimum or trough levels of 15–20 mcg/mL should be targeted in patients with severe infections, which targets four to five times the MIC [32,35,53].

Therapeutic drug monitoring should be used in patients receiving vancomycin therapy to monitor for efficacy and safety in patients with changing kinetics [32,53]. Because one measure of vancomycin's efficacy is fT>MIC, studies have investigated continuous versus intermittent administration, but because of conflicting evidence, the 2009 Infectious Diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Disease Pharmacists consensus recommendations suggest that continuous infusion regimens are unlikely to substantially improve patient outcomes [53]. A systematic review and meta-analysis that included more recently published literature found a lower incidence of nephrotoxicity in patients receiving continuous infusion compared with those receiving intermittent infusion (RR: 0.61, 95% confidence interval 0.47–0.8; p < 0.001), but no differences in treatment failure or death between the two groups [54].

Fluoroquinolones inhibit DNA gyrase causing breakage of DNA strands and have coverage of some gram-positive and gram-negative bacteria, although resistance to many organisms exists currently [55]. Because of high rates of resistance, most institutions cannot use fluoroquinolones as empiric monotherapy, especially for nosocomial infections [35,56]. Fluoroquinolones exhibit primarily concentration dependence with some time dependence, and the target AUC/MIC ratio should be ≥125 [35]. Fluoroquinolones have good tissue penetration because of their high Vd [35]. Because fluoroquinolones are lipophilic antibiotic agents, increased Vd from fluid resuscitation has minimal effects on tissue concentrations [42]. In patients with pathogens with lower MICs, higher doses of fluoroquinolones (ciprofloxacin 1200 mg/d) may achieve adequate AUC/MIC ratios; however, in organisms with higher MICs, attainment of pharmacodynamic parameters may not be possible [35,56 –58]. Dose increases to try to obtain adequate pharmacodynamic characteristics may be limited by adverse effects, and inadequate AUC/MIC ratios may be associated with selection of resistant bacterial strains [35].

Daptomycin binds to components of the cell membrane, causing rapid depolarization, inhibiting intracellular synthesis of deoxyribonucleic acid, ribonucleic acid, and proteins, and it provides bactericidal activity against most gram-positive organisms [59]. Daptomycin has concentration-dependent activity with AUC/MIC being the pharmacodynamic parameter that best describes its activity [60]. Bacteriostatic activity has been observed with an AUC/MIC >400, and bactericidal effects have been seen with AUC/MIC >800 [60,61]. Patients with documented S. aureus infections have higher rates of clinical success (94% vs. 73%; p = 0.05) and microbiologic success (93% vs. 68%; p < 0.05) when treated with daptomycin 8 mg/kg compared with 6 mg/kg with no additional toxicity [62]. Renal function has a significant influence on daptomycin clearance, with decreased renal function being associated with decreased daptomycin clearance, necessitating renal adjustment [60].

Tigecycline inhibits bacterial protein synthesis and has activity against a variety of gram-positive pathogens, including MRSA, gram-negative bacterial pathogens, as well as atypical and anaerobic pathogens, but does not have activity against Pseudomonas sp., Proteus sp., and Providencia sp. [63]. Tigecycline is lipophilic with a large Vd; therefore, it is minimally affected by fluid resuscitation [3,42]. Tigecycline is both time- and concentration-dependent; therefore, the AUC/MIC ratio is the pharmacodynamic parameter that best measures its efficacy because of its long half-life and prolonged post-antibiotic effect, although a specific AUC/MIC value has not been identified [3,42]. Tigecycline requires no adjustment in renal dysfunction or mild to moderate hepatic dysfunction and undergoes biliary excretion with only 15% eliminated unchanged in the urine [3,42]. Overall, pharmacokinetics and pharmacodynamics are minimally affected by sepsis and critical illness [3].

Conclusion

Critically ill patients have alterations in pharmacokinetic parameters that can lead to inappropriate and inadequate dosing of antimicrobial agents. This can lead to ineffective treatment regimens and increased toxicity. It is crucial for clinicians to understand these alterations, in addition to basic pharmacodynamic principles and how they affect the classes of antimicrobial agents used most commonly in the ICU. Individualized dosing regimens are becoming more important given these alterations, in addition to increased use of organ support systems.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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