The Use of Extended-Interval Aminoglycoside Dosing Strategies for the Treatment of Moderate-to-Severe Infections Encountered in Critically Ill Surgical Patients

Abstract

Background:

Extended-interval dosing strategies have been developed to exploit the concentration-dependent bactericidal activity and time-dependent host toxicity associated with aminoglycoside the therapy. The ability of published extended-interval dosing nomograms to achieve optimal pharmacodynamic endpoints may be limited in certain critically ill surgical patients.

Methods:

Review of pertinent English language literature. Presentation of descriptive, graded recommendations for extended-interval aminoglycoside dosing in critically ill surgical patients.

Results:

Aminoglycoside dosing considerations in critically ill surgical patients should attempt to maximize the bacterial and host pharmacodynamic attributes of these agents. Empirically, extended-interval aminoglycoside doses proposed by published nomograms are reasonable for most patients; however, because of clinically meaningful variations in aminoglycoside pharmacokinetics, routine use of published extended-interval aminoglycoside dosing nomograms to determine an appropriate dosage interval is discouraged in many critically ill surgical patients. Critically ill surgical patients receiving extended-interval aminoglycoside dosages should undergo individualized pharmacokinetic analysis to characterize efficiently and more effectively plasma concentration-to-bacterial minimum inhibitory concentration (MIC) relationships and determine an appropriate dosing interval, considering site and severity of infection, plasma clearance, and the apparent post-antibiotic effect.

Conclusions:

The use of extended-interval aminoglycoside dosage regimens in critically ill surgical patients should be based on pharmacodynamic endpoints and patient-specific pharmacokinetic assessment.

Aminoglycoside antibiotics have been used for over 50 years for the treatment of gram-negative infections. Although use of aminoglycosides as monotherapy may be suboptimal for moderate-to-severe infections [1 –3], use in conjunction with other agents (e.g., β-lactam antibiotics) is common for many infections encountered in critically ill surgical patients [4 –8]. Additionally, development and progression of β-lactam and fluoroquinolone antibiotic resistance has led to resurgence of concomitant aminoglycoside therapy. In the early 1990's, it was established that aminoglycosides exhibit concentration-dependent bactericidal activity [9 –13], and time-dependent host nephrotoxicity and ototoxicity [14,15]. Greater understanding of these pharmacodynamic principles has led to the development and use of aminoglycoside dosing strategies that maximize the peak plasma aminoglycoside concentration while limiting the duration of host exposure, thus exploiting the pharmacodynamic properties of these agents [11,16,17]. Collectively, these strategies are referred to as extended-interval aminoglycoside dosing. Due to a lack of well-designed studies evaluating the efficacy of extended-interval dosing strategies on clinical endpoints in critically ill surgical patients, attainment of pharmacodynamic endpoints is a reasonable and feasible surrogate clinical aim. Although these dosing strategies are used commonly, data indicate that variations in the pharmacokinetic behavior of aminoglycosides may limit the ability of published extended-interval aminoglycoside dosing nomograms to achieve desired pharmacodynamic endpoints in critically ill surgical patients [14,18]. The most appropriate method of extended-interval aminoglycoside dosing in critically ill surgical patients, by way of pharmacodynamic endpoints, remains an issue for debate.

Methods

A computerized search of the National Library of Medicine, from 1970 through January 2009, was performed to identify pertinent basic and clinical research, as well as reviews and meta-analyses investigating: (1) The pharmacodynamic properties of aminoglycoside antibiotics; (2) efficacy and toxicity of conventional and extended-interval dosing strategies; or (3) pharmacokinetic alterations in critically ill surgical patients receiving aminoglycosides. Medical Search Headings (MeSH) used included: “Antibiotics, aminoglycoside”; “antibiotics, aminoglycoside/pharmacology”; “antibiotics, aminoglycoside/administration and dosage”; “antibiotics, aminoglycoside/therapeutic use”; “antibiotics, aminoglycoside/toxicity”; “antibiotics, aminoglycoside/pharmacokinetics”; “antibiotics, aminoglycoside/pharmacodynamics”; “treatment outcome”; “critical illness”; and “surgery”. Clinical and laboratory-based investigations, reviews, and meta-analyses evaluating the efficacy or toxicity of aminoglycoside antibiotics were selected to describe the relationship between aminoglycoside concentration and outcome. To assess the pharmacokinetic behavior of aminoglycoside antibiotics in critically ill surgical patients, prospective or retrospective pharmacokinetic investigations were included. Only prospective pharmacokinetic studies evaluating extended-interval aminoglycoside dosing strategies in this population were used for the development of dosage recommendations. In considering the pharmacokinetic behavior of aminoglycosides in critically ill surgical patients, the following data were extracted from each of the selected studies: Number of patients; number of pharmacokinetic samples per patient; mean aminoglycoside dosage; mean maximum and minimum plasma concentrations; mean aminoglycoside volume of distribution; mean elimination half-life; mean rates of aminoglycoside clearance; and infection type.

When possible, the Eastern Association for the Surgery of Trauma (EAST) guidelines for evidence-based medicine evaluation were used to assess the strength of available evidence and grade specific recommendations [http://www.east.org/tpg/primer.pdf ]. Recommendations were classified as Level 1: Convincingly justifiable based on available scientific information alone; Level 2: Reasonably justifiable by available scientific evidence and strongly supported by expert review or opinion; or Level 3: Supported by available data but adequate scientific evidence is lacking. In the absence of well-designed, patient outcome-centered studies regarding the reviewed subheading, Level Indeterminate recommendations were developed representing the opinions of the authors as reasonable and clinically feasible guidance.

Pharmacologic Foundation

Aminoglycoside antibiotics inhibit bacterial protein synthesis by binding to the 30S ribosomal subunit, resulting in disruption of mRNA function and aberrant amino acid sequencing. The rate and extent of bactericidal activity of aminoglycosides is dependent on the magnitude of aminoglycoside concentration to which a bacterium is exposed, rather than the duration of aminoglycoside exposure [9 –13]. In vitro, maximal bacterial killing is observed at an aminoglycoside concentration-to-bacterial minimum inhibitory concentration (MIC) ratio of 10 or greater [9 –13,19,20]. This concentration-dependent activity is best described clinically by the aminoglycoside plasma peak concentration:bacterial MIC. Similar to the magnitude of relationship in vitro, clinical investigations have demonstrated a plasma peak concentration:MIC ≥ 10 to be associated with a shorter time to clinical response and a greater probability of clinical cure [21 –24]. Higher peak aminoglycoside concentration:MIC also potentiates the aminoglycoside post-antibiotic effect (PAE). This phenomenon is characterized by persistent suppression of bacterial growth at sub-MIC or even undetectable aminoglycoside concentrations [10,25,26]. Although it is difficult to ascertain clinically, the PAE may last as long as 8 h (range 0.5–8 h) varying according to bacterial species, the duration of aminoglycoside exposure, bacterial MIC, and aminoglycoside concentration [10,24 –26].

In contrast to bactericidal activity, the two major host toxicities associated with aminoglycosides, nephrotoxicity and ototoxicity, are dependent on the duration of host tissue exposure, not the absolute concentration [14,15,27,28]. Therefore, these aminoglycoside-associated toxicities are better described as time-dependent rather than concentration-dependent. Although the presence of aminoglycoside in these tissues (i.e., a concentration greater than zero) is required, renal and otic cellular uptake is a saturable process, such that the magnitude of tissue concentration is self-limiting [29]. Consequently, aminoglycoside-associated nephrotoxicity and ototoxicity are related to the plasma trough, or predose, aminoglycoside concentration, as well as duration of aminoglycoside therapy [27]. Because renal and otic tissue clearance is slower than plasma clearance [29], the trough concentration serves as a surrogate for the duration of tissue exposure, such that a detectable trough concentration implies persistence of tissue concentrations [29 –31]. Time-dependent aminoglycoside-to-bacterium interactions also may have clinical implications. Following sustained exposure to aminoglycosides, many bacteria exhibit adaptive resistance through down-regulation of necessary influx pathways, leading to decreased intracellular drug concentrations [10,14,32,33].

Extended-Interval Aminoglycoside Dosing

Recommendations:

Extended-interval aminoglycoside dosing strategies should be used preferentially over conventional dosing strategies for the treatment of moderate-to-severe infections in patients in whom the systemic use of an aminoglycoside antibiotic is indicated without relative or absolute contraindication. (Level 1)

Extended-interval aminoglycoside doses should be based on the MIC of the bacterial pathogen with the goal to attain a plasma peak concentration-to-MIC ratio of at least 10 for most infections. (Level 2)

Absolute plasma peak concentrations should not exceed 30 mg/L for tobramycin and gentamicin, or 80 mg/L for amikacin. (Level 2)

Dosing intervals for extended-interval aminoglycoside dosing strategies should allow for undetectable drug concentrations (e.g., ≤0.5 mg/L) 4–6 h before the next scheduled dose. (Level 2)

The utility of extended-interval versus conventional aminoglycoside dosing in patients who are age 75 years or older, pregnant, morbidly obese (i.e., > 150% of ideal body weight), or severely burned is unknown. If extended-interval aminoglycoside therapy is used, it is reasonable to adhere to similar dosing principles as described above. Due to the potential for pharmacokinetic alterations and variability, individualized aminoglycoside pharmacokinetic analysis should be performed in these patients regardless of dosing strategy. (Level 2)

Extended-interval aminoglycoside dosing should be avoided in patients with creatinine clearance (CrCl) less than 20 mL/min. (Level 2)

Rationale: Extended-interval aminoglycoside dosing strategies (often referred to as “once-daily” dosing) have been developed based on the pharmacodynamic properties of aminoglycosides and the implications of pharmacodynamic endpoints on efficacy and toxicity. These strategies have become the standard means for aminoglycoside administration in many U.S. medical centers [34 –36]. In contrast to conventional divided dosing strategies, extended-interval dosing involves the administration of a single large dose of aminoglycoside at intervals ≥24 h (Fig. 1) [37]. In general, these dosages result in greater peak plasma concentrations, which increases the plasma peak concentration:MIC for a given pathogen, whereas the extended administration interval allows time for trough plasma concentrations to recede to sub-MIC, and often undetectable, concentrations. The potential advantages of extended-interval strategies are to: (1) Maximize the concentration-dependent bactericidal activity by optimizing the plasma peak concentration: MIC (2) minimize time-dependent toxicity by limiting the duration of renal and otic tissue aminoglycoside exposure; (3) maximize the duration of the concentration-dependent PAE; and (4) limit adaptive resistance.

Fig. 1.

Simulated concentration-versus-time curve for extended-interval and conventional dosing strategies.

Extended-interval dosing strategies have been used for moderate-to-severe infections (e.g., intraabdominal infections, pneumonia, pyelonephritis, and bacteremia) in various patient populations [11,34,38]. Overall, studies evaluating the relative efficacy and safety of extended-interval dosing regimens compared to conventional regimens have demonstrated that extended-interval strategies are either as efficacious and safe, or superior to the conventional dosing strategy comparator. Because of heterogeneous populations and small sample sizes [39], eight meta-analyses [16,17,40 –45] have been conducted to better determine the relative difference in efficacy and safety between these strategies (Table 1; it is important to note that many of the same studies were used in all of the meta-analyses). Briefly, two meta-analyses [16,45] reported a significant increase in clinical response rate with extended-interval dosing, one analysis [17] reported a significant decrease in the rate of clinical failure, and the remaining analyses demonstrated a modest trend towards improved clinical efficacy [40 –44]. Four analyses [16,17,43,45] reported no difference between the two strategies in regards to microbiologic response, whereas the two analyses evaluating mortality [43,44] reported a statistically non-significant trend towards decreased mortality with the use of an extended-interval strategy. With regards to safety, no difference among the rates of ototoxicity between the two strategies was demonstrated. Two analyses reported a significant decrease in the risk of nephrotoxicity with extended-interval strategies [41,42] whereas the remaining analyses reported no difference in the rate or risk of nephrotoxicity compared to conventional strategies [16,17,40 –45]. More recent comparisons, including one randomized, double-blind, placebo-controlled study with 123 patients [15], have demonstrated administration frequency [15], trough concentration [46], duration of aminoglycoside therapy [15,46,47], and both daily and cumulative area under the curve concentration (AUC) [15,46,47] to be associated with nephrotoxicity. Therefore, aminoglycoside toxicity is less likely with extended-interval dosing strategies because they are more often associated with decreased administration frequency, lower trough concentrations, and lower daily and cumulative AUC.

Table 1.

Overview of Published Meta-Analyses Comparing Extended-Interval and Conventional Aminoglycoside Dosing Strategies

Reference	No. studies included	No. of patients	Outcome measure	Efficacy	Nephrotoxicity	Ototoxicity
16	26	NR	Rate difference^b (95% CI)	Clinical response 3.06% (0.17% to 5.95%)* Microbiologic response 1.25% (−0.40% to 2.89%)	−0.18% (−2.17% to 1.81%)	1.38% (−0.99% to 3.75%)
17	22	>2,500	Rate difference^b (95% CI)	Clinical response 3.4% (0.2% to 6.7%)* Microbiologic response 1.7% (−2.1% to 5.4%)	−0.6% (−2.4% to 1.1%)	0.3% (−1.2% to 1.8%)
40	16	<1,200	Relative risk (95% CI)	Clinical response 1.03 (0.99 to 1.06)	0.99 (0.98 to 1.02)	0.99 (0.99 to 1.02)
41	13,12^a	NR	Odds ratio (95% CI)	Clinical response 0.79 (0.59 to 1.07)	0.70 (0.51 to 0.94)*	ND
42	18	>2,300	Odds ratio (95% CI)	Clinical response 1.47 (1.13 to 1.94)*	0.60 (0.40 to 0.86)*	0.56 (0.26 to 1.16)
43	17	>1,600	Relative risk (95% CI)	Microbiologic response 1.02 (0.99 to 1.05) Mortality 0.91 (0.63 to 1.31)	0.87 (0.6 to 1.26)	0.67 (0.35 to 1.28)
44	19	>3,000	Relative risk (95% CI)	Clinical response 0.83 (0.57 to 1.21) Mortality 0.87 (0.58 to 1.30)	0.78 (0.57 to 1.07)	1.09 (0.60 to 1.75)
45	20	>2,800	Rate difference^b (95% CI)	Clinical response 3.5% (0.5% to 6.5%)* Microbiologic response 3.4% (−0.9% to 7.7%)	1.3% (−3.1% to 5%)	−0.4% (−0.2% to 0.9%)

CI, confidence interval; NR, not reported; ND, not done.

13 studies were included for efficacy evaluation and 12 studies were included in nephrotoxicity evaluation.

Frequency in extended-interval dose arm minus frequency in conventional dose arm.

p < 0.05.

The most commonly cited extended-interval aminoglycoside dosing strategy is a nomogram developed at the Hartford Hospital in Hartford, CT [34]. Based on the highest MIC of gentamicin and tobramycin-susceptible gram-negative bacteria encountered in their facility (Pseudomonas aeruginosa with an MIC of 2 mg/L), an empiric dosage of 7 mg/kg of gentamicin or tobramycin (25 mg/kg for amikacin) is administered. The dose calculation was based on actual body weight unless the patient was greater than 120% of ideal body weight, in which case an adjusted body weight (adjusted body weight = 0.4 * [actual body weight − ideal body weight] + ideal body weight was utilized). Using population-based estimates for aminoglycoside volume of distribution (Vd., 0.25–0.30 L/kg), this dose was chosen to attain a gentamicin or tobramycin peak plasma concentration of 21–28 mg/L (80–90 mg/L for amikacin). These peak plasma concentrations result in, at minimum, corresponding plasma peak concentration:MIC ranging 10.5 to 14 for gram-negative organisms with gentamicin or tobramycin MICs ≤ 2 mg/L.

The extended-interval administration frequency is determined based on a single aminoglycoside concentration obtained 8–12 h after administration of the first dose. The concentration is plotted against three different plasma concentration-versus-time curves representing three different rates of aminoglycoside clearance derived from population estimates. These curves correspond to dosing schedules of 24, 48, and 72-hours, with the goal to achieve undetectable plasma concentrations 4–6 h before the next scheduled dose. It is presumed that during this 4–6 h interval, bacterial killing continues as a consequence of the PAE, while renal and otic tissue concentrations decrease. Due to this drug-free interval, steady state (i.e., the point at which the rate of drug input equals the rate of drug elimination) is not achieved; therefore, daily pharmacokinetic analysis in stable patients is not warranted.

Despite the widespread adoption of extended-interval aminoglycoside strategies, this approach has not been studied in several clinical settings. In the setting of aminoglycoside susceptible gram-negative urinary tract infections, aminoglycosides are concentrated in the urine and achieve ≥10 X MIC with conventional dosing. Whereas prolongation of the dosing interval to allow trough levels to reach undetectable levels seems rational, this approach has not been studied. Also, the utility of extended-interval dosing in elderly, pregnant, or morbidly obese (i.e., >150% of ideal body weight) patients is unknown. Extended-interval aminoglycoside dosing should be avoided in patients with CrCl less than 20 mL/min [38].

Pharmacokinetic Analysis for Critically Ill Surgical Patients

Recommendations:

Patient-specific pharmacokinetic data (e.g., plasma half-life; volume of distribution; peak and trough plasma concentrations) rather than published nomograms should be used to evaluate the ability of a specific aminoglycoside dosage regimen to achieve preferred pharmacodynamic endpoints in critically ill surgical patients. (Level 2)

To improve clinical efficiency and accuracy of pharmacokinetic analysis, two measurable plasma concentrations obtained after the first dose and at least 6–8 hours apart (e.g., 3- and 10-h post-dose concentrations) can be used to estimate the peak concentration and determine an appropriate dosing interval for most critically ill surgical patients. (Level Indeterminate)

Follow-up pharmacokinetic analysis should be done in patients with: (1) A recent change in aminoglycoside dosage regimen; (2) diminished response in clinical course; (3) rapidly changing renal function; (4) hemodynamic instability; or (5) length of aminoglycoside therapy exceeding seven days. (Level 2)

Rationale: Critically ill surgical patients exhibit inter- and intra-patient variability in aminoglycoside pharmacokinetics [18,48]. From a pharmacodynamic perspective, the most relevant aminoglycoside pharmacokinetic alterations are changes in Vd and plasma clearance rate. Change in Vd directly affects the ability of a specific dosage regimen to achieve the desired plasma peak concentration:MIC whereas changes in plasma clearance may affect the duration of host tissue exposure or allow aminoglycoside concentrations to become undetectable short of the apparent PAE window. These considerations are relevant given that critically ill patients are at increased risk for infection-related, as well as aminoglycoside-related adverse outcomes [49 –52].

Despite a paucity of clinical comparison data for extended-interval aminoglycoside dosing strategies in critically ill surgical patients, the pharmacodynamic principles that support extended-interval dosing have been extrapolated to this population [3 –9,34,36 –38]. However, published nomograms based on discrete general population pharmacokinetic assumptions fail to represent the complexity and variability of aminoglycoside behavior in these and other critically ill patients. As such, application of the principles of extended-interval aminoglycoside dosing strategies to critically ill patients is likely best achieved by individual pharmacokinetic analysis. This approach may provide a more accurate and relevant means to anticipate the magnitude of pharmacokinetic alteration and quantify the attainment of related pharmacodynamic endpoints and associated clinical benefits [52].

Volume of Distribution and Dose Determination

Recommendations:

Initial empiric extended-interval aminoglycoside doses should be 7 mg/kg for gentamicin and tobramycin, and 25 mg/kg for amikacin in critically ill surgical patients with known or suspected moderate or severe infection for whom aminoglycoside therapy is indicated. (Level 2)

Extended-interval aminoglycoside doses should be based on actual body weight unless this weight is greater than 120% of ideal body weight, then an adjusted body weight (e.g., adjusted body weight = 0.4 * [actual body weight − ideal body weight] + ideal body weight) should be utilized. (Level 2)

A patient-specific post-distributional aminoglycoside peak concentration should be measured or estimated using formal pharmacokinetic analysis. (Level 2)

Two measurable plasma concentrations obtained after the first dose and at least 6–8 h apart (e.g.,3- and 10-h post-dose concentrations) can be used to estimate the aminoglycoside peak concentration and Vd using formal pharmacokinetic analysis. (Level Indeterminate)

A measured post-distributional peak concentration can be obtained between 30–60 min after infusion of the first dose; however, this may underappreciate aminoglycoside distribution time. (Level Indeterminate)

Following pharmacokinetic estimation of Vd, extended-interval aminoglycoside dosages should be targeted to attain a plasma peak concentration:MIC of at least 10. Absolute plasma peak concentrations should not exceed 30 mg/L for tobramycin and gentamicin, or 80 mg/L for amikacin. (Level 2)

Rationale: Under non-steady state conditions, such as extended-interval aminoglycoside dosing, the aminoglycoside peak plasma concentration is inversely proportional to Vd. For a given dose, a doubling of the Vd would result in a 50% decrease in the peak plasma concentration and a 50% decrease in plasma peak concentration:MIC ratio [18]. Therefore, in patients receiving extended-interval dosing, Vd is a major determinant of plasma peak concentration:MIC. Clinically significant alterations in aminoglycoside Vd in critically ill surgical patients have been demonstrated [49,53 –76]. Most studies report a significant increase in mean Vd compared to case controls or population estimates [53,55,57,59 –61,63,64,72,73,75]. Pooled analysis also demonstrates a great deal of variability of Vd with reported ranges spanning 0.06 to 0.77 L/kg and reported means ranging from 0.20 to 0.49 L/kg. Although expansion of Vd is likely due to many identifiable, but complex factors (e.g., capillary leak, resuscitation volume, trauma, mechanical ventilation, systemic inflammatory response syndrome, and sepsis), it is difficult to predict the magnitude and time-course of the expansion without patient-specific pharmacokinetic evaluation.

Until the late 1990's, use of the Hartford nomogram in critically ill surgical patients had not been evaluated [72 –79]. Coupled by the widespread use of this nomogram and evidence supporting clinically meaningful changes in Vd in these patients, recent investigations determined the population-specific pharmacokinetic behavior of this extended-interval nomogram. In these studies, patients received 7 mg/kg, according to protocol, with the dosing interval decided based on a single plasma concentration obtained between 8–12 h as dictated by the Hartford nomogram. Mean volumes of distribution ranged from 0.28–0.49 L/kg with intrapatient variability noted within all of the study populations. Consequently, to achieve a peak plasma concentration 20–30 mg/L, as targeted by the original nomogram, corresponding dosages of 5.9–10.3 mg/kg, respectively, would have been required for this range of Vd. As such, doses used in published extended-interval aminoglycoside nomograms may underpredict the aminoglycoside Vd and result in lower-than-targeted plasma peak concentrations. Although these studies did not evaluate doses exceeding 7 mg/kg, these data indicate that individualization of dose would have been required to achieve plasma peak concentration:MIC of at least 10 for pathogens with MIC equal to 2 mg/L.

Plasma Clearance and Dosing Interval

Recommendations:

Estimation of appropriate extended-interval aminoglycoside dosing intervals in critically ill patients to allow for undetectable drug concentrations 4–6 h before the next scheduled dose is most reliable and preferred through patient-specific pharmacokinetic analysis. (Level 2)

Efficient and accurate estimation of aminoglycoside pharmacokinetics is reasonable using two measurable plasma concentrations obtained after the first dose and at least 6–8 h apart (e.g., 3- and 10-h post-dose concentrations). (Level Indeterminate)

Appropriate aminoglycoside dosing intervals for critically ill patients with estimated CrCl > 60 mL/min should be determined using patient-specific pharmacokinetic analysis, as published nomograms underpredict aminoglycoside clearance in these patients. (Level 2)

Appropriate aminoglycoside dosing intervals for critically ill patients with CrCl 20–60 mL/min should be determined using patient-specific pharmacokinetic analysis (Level 2) or published nomograms (e.g., Hartford nomogram) by way of a single plasma concentration obtained 8–12 h after dose administration (Level 3).

Extended-interval aminoglycoside dosing strategies are not recommended for patients with CrCl <20 mL/min due to risk of aminoglycoside accumulation and prolonged otic and renal tissue exposure. Risk:benefit should be weighed carefully for aminoglycoside use regardless of the dosing strategy in these patients (Level 2).

Rationale: Intra- and inter-patient variability in aminoglycoside clearance have also been demonstrated in critically ill surgical patients [14,72,73,76 –79]. Insufficient clearance is dealt with routinely by standard pharmacokinetic analysis and corresponding dose or interval adjustment(s). Conversely, rapid clearance rates create a challenge for published extended-interval nomograms to predict an administration interval that provides a drug-free period not exceeding the reported 4–6 h aminoglycoside PAE. In patients with CrCl between 20–60 mL/min, the Hartford nomogram has predicted dosing intervals accurately, yielding seemingly adequate drug-free periods [71,72]. In patients with CrCl >60 mL/min, a random plasma concentration plotted according to the Hartford nomogram would likely prescribe a once-daily (every 24 h) dosing interval. This interval should yield an undetectable pre-dose concentration; however, it may underestimate the appropriate administration frequency, allowing drug-free periods ≥12 h in 20–60% of patients [76,78]. This is period of time is well beyond the duration of the presumed aminoglycoside PAE [72 –74,76]. Although speculative, drug-free periods extending beyond the apparent PAE of aminoglycosides may allow for increased bacterial growth and, at least partially, account for clinical failure.

Future Considerations

Because the bactericidal activity of aminoglycosides and patient outcome have been associated with the peak concentration:MIC, targeting peak plasma concentrations according to the MIC of the infecting gram-negative organism(s) seems to be a relevant aim. However, using a plasma peak concentration:MIC may be misguided for several reasons. First, the highly polar nature of aminoglycosides results in variable and often limited distribution into infected secretions and tissues. For example, 5% of the plasma concentration penetrates into the cerebrospinal fluid whereas approximately 30% of the plasma concentration penetrates lung interstitium [80,81]. Therefore, based on their pharmacodynamic properties, targeting specific tissue concentrations in order to achieve a local peak concentration:MIC ≥10 may be a more appropriate therapeutic goal. Lack of available bedside technology, prohibits the determination of local tissue concentrations. Second, because aminoglycosides possess a PAE, the “all-or-none” nature of MIC-based endpoints is limiting. It has been suggested that more dynamic estimates of pharmacokinetic-pharmacodynamic interactions mimicking the physiologic environment of host, organism, and antibiotic (e.g., kill curves) could provide more relevant information regarding pharmacodynamic endpoints. Lastly, the primary role of aminoglycosides in the treatment of moderate-to-severe infections is most often as an adjunct to other agents. For this reason, the importance of optimizing the aminoglycoside concentration, be it systemically, locally, or otherwise, has been argued [11]. Until local sampling modalities (e.g., microdialysis [82]) make their way to the bedside and are proved to be relevant to patient outcome, and data supporting the therapeutic use of direct administration to the site of infection (e.g., aerosolized administration [83]) are supportive, dosing strategies that proficiently maximize the plasma peak concentration:MIC and minimize host toxicity will continue to be the best therapeutic option.

Summary

The use of aminoglycoside antibiotics to manage critical illness-related infections remains common and is increasing because of antibiotic resistance. As understanding of the pharmacodynamic properties of these agents has progressed, extended-interval dosing has emerged as a safe, effective, and convenient method of systemic administration. Although pharmacokinetic alterations occurring in certain critically ill surgical patients may preclude the use of published nomograms in this population, the pharmacodynamic principles on which they are designed remain important. Due to the potential for clinically meaningful variations in aminoglycoside Vd and plasma clearance to occur in certain critically ill surgical patients, individualization of aminoglycoside dosage regimens should be based on patient-specific estimates of Vd and plasma clearance. Although untested related to patient outcome, pharmacokinetic data suggest that application of optimal aminoglycoside pharmacodynamic principles through individualization of aminoglycoside dosage may result in doses exceeding those recommended by published nomograms administered more frequently than every 24 h in certain critically ill surgical patients. Interdisciplinary collaboration for pharmacokinetic analysis within the critical care team is encouraged.

Acknowledgments

On behalf of the Therapeutic Agents Committee of the Surgical Infection Society the authors thank Joseph T. DiPiro, Pharm.D. for his comments regarding the direction of this manuscript.

Author Disclosure Statement

The authors have no conflicts of interest to disclose.

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