|Year : 2017 | Volume
| Issue : 3 | Page : 340-346
Optimisation of antimicrobial dosing based on pharmacokinetic and pharmacodynamic principles
Grace Si Ru Hoo1, Yi Xin Liew2, Andrea Lay-Hoon Kwa3
1 Department of Pharmacy, Tan Tock Seng Hospital, Singapore
2 Department of Pharmacy, Singapore General Hospital, Singapore
3 Department of Pharmacy, Singapore General Hospital; Emerging Infectious Diseases, Duke-National University of Singapore; Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore
|Date of Web Publication||12-Oct-2017|
Andrea Lay-Hoon Kwa
Department of Pharmacy, Singapore General Hospital, Outram Road 169 608
Source of Support: None, Conflict of Interest: None
While suboptimal dosing of antimicrobials has been attributed to poorer clinical outcomes, clinical cure and mortality advantages have been demonstrated when target pharmacokinetic (PK) and pharmacodynamic (PD) indices for various classes of antimicrobials were achieved to maximise antibiotic activity. Dosing optimisation requires a good knowledge of PK/PD principles. This review serves to provide a foundation in PK/PD principles for the commonly prescribed antibiotics (β-lactams, vancomycin, fluoroquinolones and aminoglycosides), as well as dosing considerations in special populations (critically ill and obese patients). PK principles determine whether an appropriate dose of antimicrobial reaches the intended pathogen(s). It involves the fundamental processes of absorption, distribution, metabolism and elimination, and is affected by the antimicrobial's physicochemical properties. Antimicrobial pharmacodynamics define the relationship between the drug concentration and its observed effect on the pathogen. The major indicator of the effect of the antibiotics is the minimum inhibitory concentration. The quantitative relationship between a PK and microbiological parameter is known as a PK/PD index, which describes the relationship between dose administered and the rate and extent of bacterial killing. Improvements in clinical outcomes have been observed when antimicrobial agents are dosed optimally to achieve their respective PK/PD targets. With the rising rates of antimicrobial resistance and a limited drug development pipeline, PK/PD concepts can foster more rational and individualised dosing regimens, improving outcomes while simultaneously limiting the toxicity of antimicrobials.
Keywords: Antimicrobial dosing, optimisation, pharmacokinetic, pharmacodynamic
|How to cite this article:|
Hoo GS, Liew YX, Kwa AL. Optimisation of antimicrobial dosing based on pharmacokinetic and pharmacodynamic principles. Indian J Med Microbiol 2017;35:340-6
|How to cite this URL:|
Hoo GS, Liew YX, Kwa AL. Optimisation of antimicrobial dosing based on pharmacokinetic and pharmacodynamic principles. Indian J Med Microbiol [serial online] 2017 [cited 2018 Dec 12];35:340-6. Available from: http://www.ijmm.org/text.asp?2017/35/3/340/216629
| ~ Introduction|| |
Antimicrobial agents improve the health of individuals with an infection by preventing the growth of, or killing, the pathogen(s) at the primary site of infection. To prevent or minimise resistance, dosing regimens should exhibit high efficacy not only to susceptible wild-type bacteria but, preferably, also to mutated bacteria with varying degrees of resistance that may exist in low numbers within the population. While suboptimal dosing of antimicrobials has been attributed to poorer clinical outcomes, clinical cure and mortality advantages have been demonstrated when target pharmacokinetic (PK) and pharmacodynamic (PD) indices for various classes of antimicrobials were achieved to maximise antibiotic activity.,
Adequate antimicrobial dosing to achieve PK/PD targets in individual patients continues to be a challenge. The labelled doses are frequently obtained from studies only done in healthy volunteers and often do not account for PK and PD differences among healthy and septic patients, as well as among different patient populations. Dosing optimisation of the antimicrobial agents requires a good knowledge of mechanisms involved in the distribution of the antibiotic concentration in the body (i.e. PK) and the effect of the antibiotics (i.e. PD) on the pathogen.
This review serves to provide a foundation in PK/PD principles for the commonly prescribed antibiotics (β-lactams, vancomycin, fluoroquinolones and aminoglycosides), as well as dosing considerations in special populations (critically ill and obese patients). It aims to assist clinicians and pharmacists in choosing dosing regimens that maximises clinical benefit while minimising the risk of toxicity.
| ~ Pharmacokinetic/pharmacodynamic Principles|| |
PK describes the fundamental processes of absorption, distribution, metabolism and elimination and the resulting concentration-versus-time profile of an agent administered in vivo. By applying PK principles, a clinician can determine whether an appropriate dose of antimicrobial will reach the pathogen(s). PK studies describe parameters such as peak concentration (Cmax) and cumulative exposure (area-under-the-concentration-time curve [AUC]) for a given time period [Figure 1].
|Figure 1: Concentration–time curve and pharmacokinetic and pharmacodynamic studies describing antimicrobial efficacy|
Click here to view
In addition, the antimicrobial's physicochemical properties must also be considered to predict its disposition [Table 1]. First, the relative solubility of the antimicrobial has a significant impact on its volume of distribution (Vd) and will affect the selection of agents and doses expected to attain adequate penetration to the site of infection. Because infections can occur outside the vascular system, the antibiotic concentration measured in the plasma is often only a surrogate for the true concentration at the site of infection and may over- or under-estimate the actual antimicrobial concentration that will reach the pathogen. Certain anatomic compartments, including bone, cerebrospinal fluid and lungs, are penetrated poorly by some antibiotics. For example, most β-lactams have bone:serum ratios between 0.1 and 0.3 while that for vancomycin is estimated to be 0.2. This is consistent with the hydrophilic nature of the antibiotics and the higher range of doses would be necessary when treating osteomyelitis. In contrast, fluoroquinolones are lipophilic and have high Vd and hence, are able to achieve higher bone:serum ratios ranging from 0.35 (ciprofloxacin) to 0.75 (levofloxacin). A review on PK/PD for various sites of infection has been done. In general, a high Vd implies that the drug is distributed extensively to tissue (lipophilic), whereas a low Vd that is similar to that of extracellular water (0.1–0.7 L/kg) suggests that the drug is concentrated in the plasma (hydrophilic). Fluid resuscitation or the physiologic derangements occurring with increased severity of illness have been shown to increase the Vd of antimicrobials and become significant in septic or critically ill patients because hydrophilic antibiotics will require use of loading doses to ensure early achievement of therapeutic concentrations. Lipophilic antibiotics, on the other hand, are not greatly influenced by changes in fluid volume and may not require alterations in initial dosing.,,
As albumin is the primary plasma-binding protein for most antibiotics, its concentrations should be considered when implementing and adjusting dosing regimens. Previously defined as a serum albumin concentration <25 g/L, hypoalbuminaemia has a direct impact on the PK of antibiotics, particularly on those antibiotics that are highly protein-bound such as ceftriaxone and ertapenem., With low plasma albumin, there is an increase of the unbound drug. This is important as only the unbound drug can exert antimicrobial effects. With an increase in the unbound drug, hypoalbuminaemia likely increases the Vd and clearance of an antimicrobial, leading to lower and possibly suboptimal concentrations towards the end of the dosing interval.
Elimination is the final PK parameter to consider. The kidney can excrete antimicrobials and their metabolites by glomerular filtration or by proximal tubular secretion. Drugs that are hydrophilic and usually subject to renal clearance are also commonly cleared by dialysis. Large molecules (>1000 Da), such as vancomycin, are poorly cleared by haemodialysis although the availability of high-flux filters has increased the clearance of these drugs. Smaller molecules, such as β-lactam and aminoglycoside antibiotics, are largely cleared by haemodialysis, although the extent of clearance is typically lesser than with normal renal function. While renal elimination can be reduced in the setting of acute kidney injury or renal failure, hyperdynamic conditions such as sepsis, increased ventricular preload following aggressive fluid resuscitation and vasopressors, may augment renal clearance by increased renal perfusion to as much as triple the normal rate and may be associated with treatment failure despite appropriate choice of antimicrobial agent.,,
Antimicrobial pharmacodynamics is the relationship between the antimicrobial concentration and the observed effect on the target pathogen in the body. The major indicator of the effect of the antibiotics is the minimum inhibitory concentration (MIC), which is defined as the minimum concentration of the antimicrobial agent that is able to inhibit the bacterial growth. The quantitative relationship between a PK and microbiological parameter is known as a PK/PD index, which describes the relationship between dose administered and the rate and extent of bacterial killing.
Three PK/PD indices describe the optimal killing associated with antibiotics [Figure 1]: (i) f T > MIC, which is the amount of time that the unbound (f) drug concentration in the plasma that remains above the MIC of the infecting organism; (ii) f Cmax/MIC, which is the ratio between the maximum concentration (Cmax) of the unbound drug and the MIC and (iii) AUC/MIC, which is the ratio of the 24-hour AUC and the MIC.
An additional factor that affects antimicrobial pharmacodynamics is the agent's post-antibiotic effect (PAE), which quantifies the persistence of bacterial suppression after drug levels are less than the MIC, thus adding to the overall duration of antimicrobial effect. In general, agents that alter protein or nucleic acid synthesis, such as aminoglycosides and fluoroquinolones, tend to display a prolonged PAE against any susceptible organism, as it takes considerably longer for bacteria to regenerate these elements compared to cell wall components., Thus, longer intervals between doses are possible without compromising treatment efficacy., On the contrary, β-lactams maintain virtually no PAE against Gram-negative pathogens (≤1 hour), often requiring multiple daily doses to ensure adequate coverage. An exception is the carbapenems, which have shown prolonged PAEs of ],, hours against Gram-negative pathogens, consistent with their lower f T > MIC requirement compared to other β-lactams.,,
β-lactams (penicillins, cephalosporins and carbapenems) are time-dependent and PD effect on the pathogen is affected by the cumulative percentage of time that the free drug concentration exceeds the MIC (f T > MIC). For bacteriostasis, the concentration of free drug must exceed the MIC for 35%–40%, 30% and 20% of the dosing interval for cephalosporins, penicillins and carbapenems, respectively. Achievement of the maximal bactericidal effect requires 60%–70%, 50% and 40% coverage, respectively, for these β-lactam classes. To improve PK/PD target attainment, β-lactams can be administered at increased doses, increased frequency or by an extended or continuous infusion, along with an initial loading dose.
Numerous studies have shown that extended infusion (3 to 4 hours) or continuous infusion allows the maintenance of concentrations above the MIC for a longer period within the dosing interval and has a greater likelihood of achieving PK/PD targets than standard intermittent bolus dosing. It capitalises on the PD properties of β-lactams to maximise bacterial killing, therefore potentially improving clinical outcomes., Several meta-analyses/reviews have been conducted to compare clinical benefits of prolonged (i.e., extended and continuous) infusion versus intermittent boluses.,,,,,,,,
However, to date, the clinical advantages of prolonged infusion remain non-conclusive. Potential reasons that could have given rise to conflicting results of these studies include low methodological study quality and small sample sizes, heterogeneous patient populations, inclusion of patients with a low level of illness severity and infections due to highly susceptible pathogens, different dosing regimens between comparative groups and concomitant antibiotic administration. Changing all patients from standard intermittent bolus dosing to extended or continuous infusion may not be warranted and may not confer any therapeutic advantage. Logistical concerns and practical challenges associated with prolonged infusion also exist. Most β-lactam antibiotics are stable for at least 24 hours at room temperature, and thus can be administered as a 24-hour continuous infusion or as extended infusion. However, certain β-lactams including the carbapenems (imipenem, meropenem and doripenem), ampicillin, and the newest cephalosporin, ceftaroline, are not stable at room temperature for a full 24 hours. As a result, these antibiotics are better suited for administration as an extended infusion to enhance PD exposure while retaining stability. Additional factors to consider for prolonged infusion include limited intravenous access, compatibility with concomitant drugs, and restriction of patient mobility. Prolonged infusion is likely to have the greatest benefit in the critically ill and/or in patients with infections secondary to pathogens with higher MICs, and its use should be rationalised by clinicians based on risk factors and clinical setting.,,
β-lactam therapeutic drug monitoring (TDM) has not been widely investigated because of the wide therapeutic window associated with this class of antimicrobials. It is likely not warranted with relatively mild infections and/or a low risk of less susceptible pathogens. However, in populations with grossly varied and unpredictable PK such as in critically ill, obese, burns and febrile neutropenia patients, or those with infections due to pathogens with high MICs, β-lactam TDM may bear more clinical relevance. The advantage of β-lactam TDM is that it provides actual measurements of serum antibiotic exposures so that dosing can be adapted to ensure optimal exposures are achieved. Albeit theoretical benefits, few studies have reported the results of a β-lactam TDM programme. The absence of a prospective randomised controlled trial demonstrating either a clinical or an economic benefit of such an intervention makes the role of TDM for β-lactam equivocal.,
In renally impaired patients, reduction in dose instead of frequency is the optimal strategy in reducing drug accumulation, but ensuring the f T > MIC is maintained.
Vancomycin is a classic example of an antimicrobial that exhibits killing when AUC/MIC is maximised. This parameter allows flexibility in selection of a dosing regimen as either adjusting the dose or frequency will result in identical AUC values. A PK/PD target of AUC/MIC ≥400 has been advocated to achieve clinical improvement and microbiologic eradication of Staphylococcus aureus pneumonia and bacteraemia.,, A 2- to 4-fold reductions in mortality were observed with attainment of these AUC/MIC thresholds.,,
As it can be challenging in the clinical setting to obtain multiple serum vancomycin concentrations to determine the AUC and subsequently calculate the AUC/MIC, trough serum concentration is often used as a surrogate marker for AUC and is recommended as the most accurate and practical method to monitor the efficacy of vancomycin. The minimum vancomycin trough concentration would have to be at least 15 mg/L to generate the target AUC/MIC of 400 for a pathogen with an MIC of 1 mg/L. On the basis of potentially improved penetration of vancomycin and better clinical outcomes for complicated infections such as bacteraemia, endocarditis, osteomyelitis, meningitis and hospital-acquired pneumonia caused by S. aureus, a consensus paper in 2009 recommends targeting serum trough concentrations of 15–20 mg/L to increase the probability of attaining the PK/PD target of AUC/MIC ≥400. In patients with normal renal function, this target is not achievable with conventional dosing methods if the MIC is ≥2 mg/L, and alternative choice of antimicrobial therapy should be considered. Patients with initial troughs >20 mg/L were significantly more likely to experience nephrotoxicity during therapy compared with vancomycin troughs of ],,,,,mg/L, although most vancomycin-induced nephrotoxicity were reversible and few required dialysis.,
Doses of 15–20 mg/kg given every ],,,, hours are recommended for patients with normal renal function to achieve the target trough concentrations. In critically ill patients, a loading dose of 25–30 mg/kg may be used to facilitate rapid attainment of target trough concentration., Dosages should be calculated based on actual body weight (ABW). There are limited data on dosing in obese patients – initial doses should be based on ABW and subsequently adjusted based on serum concentrations to achieve therapeutic levels.
Initial trough levels should be obtained immediately before the next dose at steady-state conditions (pre-4th dose) and are recommended for all patients at high risk of nephrotoxicity (e.g., concomitant nephrotoxic drugs), fluctuating renal function and those receiving prolonged courses of therapy (i.e., more than 3–5 days). When target trough levels are reached, once-weekly monitoring of trough levels is acceptable for haemodynamically stable patients with stable renal function. More frequent monitoring is advisable in patients who are haemodynamically unstable and should be based on clinical judgement.
Use of continuous vancomycin infusions has been proposed as a means to more consistent achievement of PK/PD targets and has been reviewed.,,, There is no difference in mortality rates nor treatment failure rates between continuous infusion versus intermittent infusion although a lower risk of nephrotoxicity in those receiving continuous infusion has been demonstrated.,,, Continuous infusion of vancomycin is currently not routinely used in clinical practice. Its use may be considered to achieve PK/PD targets in patients who persistently are unable to achieve target trough levels despite high doses.
In the absence of clinical data, similar practice is extrapolated for other Gram-positive pathogens such as Enterococcus spp. and coagulase-negative Staphylococcus spp.
Compared with other antibacterial agents, the fluoroquinolones have a flatter concentration–time curve, lower Cmax, longer half-life and less distinction between Cmax and trough concentrations. The low Cmax of fluoroquinolones may be caused by the low serum protein binding and high tissue uptake that occur with this class. AUC/MIC ratio is the major PK/PD parameter determining efficacy and outcomes of fluoroquinolones, and targets range from 125–250. AUC/MIC value of 125 or higher was associated with much higher rates of clinical and bacteriologic cure than values <125. Later investigations reported the necessity of higher values to attain similar outcomes, which may be a consequence of infecting pathogen and severity of infection. AUC/MIC values of 250 or higher resulted in faster eradication of the organisms from respiratory secretions than patients that had values of 125–250. Similarly, a study of ciprofloxacin for the treatment of Enterobacteriaceae bloodstream infections demonstrated that an AUC/MIC ≥250 was associated with a significantly greater treatment success rate.
In patients with renal impairment, dose adjustments are made by prolonging the dosing interval rather than altering the dose as fluoroquinolones have predominant concentration-dependence with time-dependence.
Few papers discussing fluoroquinolone TDM are available. However, given the decreasing susceptibility of pathogens and increasing data of PK/PD target for fluoroquinolones, TDM may have a benefit in obese patients and patients with significant burn injuries to ensure adequate dosing. More clinical data on this topic are needed.
Aminoglycosides are rapidly bactericidal and demonstrate concentration dependence, which means that bacterial killing is more profound with increasing f Cmax/MIC. Optimal clinical efficacy in the treatment of Gram-negative infections occurs with a ratio ≥8–10. In addition, aminoglycosides exhibit an extended PAE. For example, the PAE for Gram-negative organisms was between 10 hours (for Pseudomonas aeruginosa) to >12 hours (for Klebsiella pneumoniae). The third PD property of aminoglycosides is the phenomenon of adaptive resistance, which is a period of reversible resistance to bactericidal action after initial exposure. The combination of concentration-dependent killing, PAE and adaptive resistance provides the theoretical basis for higher doses given less frequently.
The use of aminoglycosides comes with risks. Nephrotoxicity occurs because of the accumulation of aminoglycosides within the proximal tubular epithelial cell in lysosomal phospholipid complexes, which eventually rupture and initiate cell death. As a result, the local renin-angiotensin system is activated, leading to local vasoconstriction and a decrease in the glomerular filtration rate. The onset is often delayed till after 5 days of aminoglycoside therapy. Uptake into the tubular epithelium is saturable, and the increase in luminal concentrations will be less than proportional to the size of the peak concentration. Once-daily dosing takes advantage of this and in addition provides a period where aminoglycosides could leach back into the lumen, reducing accumulation.
Meta-analyses have shown either equivalence or superiority for once-daily dosing in clinical efficacy, bacteriologic efficacy and nephrotoxicity. None has shown differences in auditory or vestibular toxicity or mortality rates. PK/PD dosing has revolutionised how aminoglycosides are prescribed – from thrice to once daily dosing, and has also improved their safety and efficacy. As such, extended interval dosing for aminoglycosides is widely considered the standard of care.
The recommended initial dose of amikacin is ],,,,, mg/kg and 5–7 mg/kg for gentamicin. Although aminoglycosides distribute into adipose tissue, it distributes much less than into extracellular water. ABW is used to calculate the initial dose unless the patient's weight is >20% greater than his ideal body weight (IBW) and then the adjusted body weight (AdjBW) using the formula AdjBW = IBW + 0.4 (ABW − IBW) should be used to avoid overdosing obese patients.,
Aminoglycoside TDM has been shown to significantly shorten hospitalisation, reduce nephrotoxicity and have a strong trend towards reduced mortality.,, Sampling half an hour post-administration will approximate the peak levels which is affected by Vd and has a direct reflection on efficacy. Peak level monitoring is not necessary if an adequate dose was given. However, it may be considered in patients with higher Vd such as critically ill patients, when treating multidrug-resistant organisms (MDROs) or when treating Gram-positive endocarditis. Trough levels have been used as a measure of the potential for development of toxicity. It should be taken just before next dose and preferably be kept at the lower limit of detection (<1 mg/L). If the trough levels are ≥1 mg/L, the dosing interval should be extended while maintaining the same dose to maximise bacterial killing by preserving Cmax/MIC. When treating severe sepsis or MDROs where the benefits may outweigh risks, the clinician may consider re-dosing aminoglycoside even with trough levels ≥1 mg/L. Trough levels are not necessary for patients who only received stat doses and may not necessarily be monitored in patients for whom the intended duration of aminoglycosides is <5 days with good and stable renal function. Trough level monitoring should be performed in patients who required prolonged duration of therapy, such as for endocarditis. For patients with poor or unstable renal function and are intended to have more than one dose, trough level will help guide the timing for a re-dose.
For patients receiving haemodialysis, the traditional practice is to administer half of the recommended aminoglycoside dose given to a patient with normal renal function after each haemodialysis session or during the last 30–60 min of haemodialysis. Of note, recent population PK and a few clinical studies are advocating pre-dialysis administration of aminoglycosides. This strategy theoretically allows the achievement of a high peak concentration (thereby enhancing bacterial killing), and subsequent early clearance by haemodialysis should help minimise the AUC (thereby limiting exposure and toxicity) and allows sufficient time for reversal of adaptive resistance (thereby increasing efficacy). Based on PK/PD principles, this strategy may be justified but has yet been confirmed by randomised controlled trials.
Dosing in special populations: Critically ill
Antimicrobial dosing in the critically ill can be extremely challenging. Critically ill patients have alterations in several PK parameters, such as fluid balance, drug clearance and organ function, and these patients frequently require assistance from mechanical organ support. The clinical status of critically ill patients is very dynamic, and drug dosing must be evaluated and altered frequently.
First, fluid balance may change, often increasing as a result of an inflammatory response, large-volume fluid resuscitation or diuresis. The Vd of hydrophilic drugs increases in the acute phase of critical illness because of the fluid resuscitation administered in response to the capillary leak syndrome., A larger Vd contributes to a lower antibiotic serum concentration that may lead to suboptimal bacterial killing and potential treatment failure. As such, hydrophilic antimicrobial agents frequently require a loading dose to achieve PK/PD targets rapidly.
Drug clearance is altered by changes in haemodynamics. Hyperdynamic cardiac output may increase drug clearance, whereas renal or hepatic impairment may decrease drug clearance. Bleeding and drains are also possible modes of drug elimination. In addition, renal replacement therapy or extracorporeal membrane oxygenation can increase or decrease the Vd and augment drug clearance. Antimicrobial clearance from continuous renal replacement therapy varies depending on types of membranes used, operational parameters and modes of dialysis. Numerous factors should be considered when dosing antimicrobials in such patients and have been reviewed in detail.,,
Individualisation of antibiotic dosing to improve clinical outcomes the antibiotic therapy by applying PK/PD knowledge is recommended. More comprehensive antibiotic dosing in the critically ill has been discussed.,,
Dosing in special populations: Obese patients
Obesity is associated with different physiological composition of muscle and fat compared to non-obese patients. These patients tend to also have a higher blood volume and cardiac output and are believed to have reduced perfusion of peripheral tissues. The effect of body weight on Vd depends on the lipophilicity of the drug. These factors can lead to changes in Vd and drug clearance that may necessitate different drug doses to achieve the same concentrations observed in non-obese patients. Antibiotic dosing in the obese patients has been reviewed elsewhere.,,
In summary, the knowledge of PK/PD principles is central to optimising dosing by influencing the choice and dosing strategy of an antimicrobial agent. Consideration should be given to patient, drug and pathogen factors. With the rising rates of antimicrobial resistance and a limited drug development pipeline, PK/PD concepts can foster more rational and individualised dosing regimens, improving patient outcomes while simultaneously limiting the toxicity of antimicrobials.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| ~ References|| |
Olofsson SK, Cars O. Optimizing drug exposure to minimize selection of antibiotic resistance. Clin Infect Dis 2007;45 Suppl 2:S129-36.
Roberts JA, Paul SK, Akova M, Bassetti M, De Waele JJ, Dimopoulos G, et al.
DALI: Defining antibiotic levels in Intensive Care Unit patients: Are current β-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis 2014;58:1072-83.
Roberts JA, Abdul-Aziz MH, Lipman J, Mouton JW, Vinks AA, Felton TW, et al.
Individualised antibiotic dosing for patients who are critically ill: Challenges and potential solutions. Lancet Infect Dis 2014;14:498-509.
Huttner A, Harbarth S, Hope WW, Lipman J, Roberts JA. Therapeutic drug monitoring of the β-lactam antibiotics: What is the evidence and which patients should we be using it for? J Antimicrob Chemother 2015;70:3178-83.
Onufrak NJ, Forrest A, Gonzalez D. Pharmacokinetic and pharmacodynamic principles of anti-infective dosing. Clin Ther 2016;38:1930-47.
Gonçalves-Pereira J, Póvoa P. Antibiotics in critically ill patients: A systematic review of the pharmacokinetics of β-lactams. Crit Care 2011;15:R206.
Blot SI, Pea F, Lipman J. The effect of pathophysiology on pharmacokinetics in the critically ill patient – Concepts appraised by the example of antimicrobial agents. Adv Drug Deliv Rev 2014;77:3-11.
Varghese JM, Roberts JA, Lipman J. Antimicrobial pharmacokinetic and pharmacodynamic issues in the critically ill with severe sepsis and septic shock. Crit Care Clin 2011;27:19-34.
Ulldemolins M, Roberts JA, Rello J, Paterson DL, Lipman J. The effects of hypoalbuminaemia on optimizing antibacterial dosing in critically ill patients. Clin Pharmacokinet 2011;50:99-110.
SAFE Study Investigators, Finfer S, Bellomo R, McEvoy S, Lo SK, Myburgh J, et al.
Effect of baseline serum albumin concentration on outcome of resuscitation with albumin or saline in patients in intensive care units: Analysis of data from the saline versus albumin fluid evaluation (SAFE) study. BMJ 2006;333:1044.
Pea F, Viale P, Pavan F, Furlanut M. Pharmacokinetic considerations for antimicrobial therapy in patients receiving renal replacement therapy. Clin Pharmacokinet 2007;46:997-1038.
Felton TW, Hope WW, Roberts JA. How severe is antibiotic pharmacokinetic variability in critically ill patients and what can be done about it? Diagn Microbiol Infect Dis 2014;79:441-7.
Udy AA, Roberts JA, Boots RJ, Paterson DL, Lipman J. Augmented renal clearance: Implications for antibacterial dosing in the critically ill. Clin Pharmacokinet 2010;49:1-6.
Udy AA, Baptista JP, Lim NL, Joynt GM, Jarrett P, Wockner L, et al.
Augmented renal clearance in the ICU: Results of a multicenter observational study of renal function in critically ill patients with normal plasma creatinine concentrations*. Crit Care Med 2014;42:520-7.
Mouton JW, Dudley MN, Cars O, Derendorf H, Drusano GL. Standardization of pharmacokinetic/pharmacodynamic (PK/PD) terminology for anti-infective drugs: An update. J Antimicrob Chemother 2005;55:601-7.
Craig WA. Post-antibiotic effects in experimental infection models: Relationship to in-vitro
phenomena and to treatment of infections in man. J Antimicrob Chemother 1993;31 Suppl D: 149-58.
Craig WA. Pharmacokinetic/pharmacodynamic parameters: Rationale for antibacterial dosing of mice and men. Clin Infect Dis 1998;26:1-0.
Ambrose PG, Bhavnani SM, Rubino CM, Louie A, Gumbo T, Forrest A, et al.
Pharmacokinetics-pharmacodynamics of antimicrobial therapy: It's not just for mice anymore. Clin Infect Dis 2007;44:79-86.
Vogelman B, Gudmundsson S, Turnidge J, Leggett J, Craig WA.In vivo
postantibiotic effect in a thigh infection in neutropenic mice. J Infect Dis 1988;157:287-98.
Bustamante CI, Drusano GL, Tatem BA, Standiford HC. Postantibiotic effect of imipenem on Pseudomonas aeruginosa
. Antimicrob Agents Chemother 1984;26:678-82.
Nadler HL, Pitkin DH, Sheikh W. The postantibiotic effect of meropenem and imipenem on selected bacteria. J Antimicrob Chemother 1989;24 Suppl A:225-31.
Hanberger H, Svensson E, Nilsson LE, Nilsson M. Control-related effective regrowth time and post-antibiotic effect of meropenem on gram-negative bacteria studied by bioluminescence and viable counts. J Antimicrob Chemother 1995;35:585-92.
Lodise TP Jr., Lomaestro B, Drusano GL. Piperacillin-tazobactam for Pseudomonas aeruginosa
infection: Clinical implications of an extended-infusion dosing strategy. Clin Infect Dis 2007;44:357-63.
Mohd Hafiz AA, Staatz CE, Kirkpatrick CM, Lipman J, Roberts JA. Continuous infusion vs. Bolus dosing: Implications for beta-lactam antibiotics. Minerva Anestesiol 2012;78:94-104.
Korbila IP, Tansarli GS, Karageorgopoulos DE, Vardakas KZ, Falagas ME. Extended or continuous versus short-term intravenous infusion of cephalosporins: A meta-analysis. Expert Rev Anti Infect Ther 2013;11:585-95.
Falagas ME, Tansarli GS, Ikawa K, Vardakas KZ. Clinical outcomes with extended or continuous versus short-term intravenous infusion of carbapenems and piperacillin/tazobactam: A systematic review and meta-analysis. Clin Infect Dis 2013;56:272-82.
Roberts JA, Webb S, Paterson D, Ho KM, Lipman J. A systematic review on clinical benefits of continuous administration of beta-lactam antibiotics. Crit Care Med 2009;37:2071-8.
Tamma PD, Putcha N, Suh YD, Van Arendonk KJ, Rinke ML. Does prolonged β-lactam infusions improve clinical outcomes compared to intermittent infusions? A meta-analysis and systematic review of randomized, controlled trials. BMC Infect Dis 2011;11:181.
Shiu J, Wang E, Tejani AM, Wasdell M. Continuous versus intermittent infusions of antibiotics for the treatment of severe acute infections. Cochrane Database Syst Rev 2013;(3):CD008481.
Kasiakou SK, Sermaides GJ, Michalopoulos A, Soteriades ES, Falagas ME. Continuous versus intermittent intravenous administration of antibiotics: A meta-analysis of randomised controlled trials. Lancet Infect Dis 2005;5:581-9.
Teo J, Liew Y, Lee W, Kwa AL. Prolonged infusion versus intermittent boluses of β-lactam antibiotics for treatment of acute infections: A meta-analysis. Int J Antimicrob Agents 2014;43:403-11.
Yang H, Zhang C, Zhou Q, Wang Y, Chen L. Clinical outcomes with alternative dosing strategies for piperacillin/tazobactam: A systematic review and meta-analysis. PLoS One 2015;10:e0116769.
Chant C, Leung A, Friedrich JO. Optimal dosing of antibiotics in critically ill patients by using continuous/extended infusions: A systematic review and meta-analysis. Crit Care 2013;17:R279.
Abdul-Aziz MH, Dulhunty JM, Bellomo R, Lipman J, Roberts JA. Continuous beta-lactam infusion in critically ill patients: The clinical evidence. Ann Intensive Care 2012;2:37.
Sinnollareddy MG, Roberts MS, Lipman J, Roberts JA. B-lactam pharmacokinetics and pharmacodynamics in critically ill patients and strategies for dose optimization: A structured review. Clin Exp Pharmacol Physiol 2012;39:489-96.
Abdul-Aziz MH, Sulaiman H, Mat-Nor MB, Rai V, Wong KK, Hasan MS, et al.
Beta-lactam infusion in severe sepsis (BLISS): A prospective, two-centre, open-labelled randomised controlled trial of continuous versus intermittent beta-lactam infusion in critically ill patients with severe sepsis. Intensive Care Med 2016;42:1535-45.
Roberts JA, Norris R, Paterson DL, Martin JH. Therapeutic drug monitoring of antimicrobials. Br J Clin Pharmacol 2012;73:27-36.
Cotta MO, Roberts JA, Lipman J. Antibiotic dose optimization in critically ill patients. Med Intensiva 2015;39:563-72.
Housman ST, Kuti JL, Nicolau DP. Optimizing antibiotic pharmacodynamics in hospital-acquired and ventilator-acquired bacterial pneumonia. Clin Chest Med 2011;32:439-50.
Moise-Broder PA, Forrest A, Birmingham MC, Schentag JJ. Pharmacodynamics of vancomycin and other antimicrobials in patients with Staphylococcus aureus
lower respiratory tract infections. Clin Pharmacokinet 2004;43:925-42.
Kullar R, Davis SL, Levine DP, Rybak MJ. Impact of vancomycin exposure on outcomes in patients with methicillin-resistant Staphylococcus aureus
bacteremia: Support for consensus guidelines suggested targets. Clin Infect Dis 2011;52:975-81.
Brown J, Brown K, Forrest A. Vancomycin AUC24/MIC ratio in patients with complicated bacteremia and infective endocarditis due to methicillin-resistant Staphylococcus aureus
and its association with attributable mortality during hospitalization. Antimicrob Agents Chemother 2012;56:634-8.
Holmes NE, Turnidge JD, Munckhof WJ, Robinson JO, Korman TM, O'Sullivan MV, et al.
Vancomycin AUC/MIC ratio and 30-day mortality in patients with Staphylococcus aureus
bacteremia. Antimicrob Agents Chemother 2013;57:1654-63.
Zelenitsky S, Rubinstein E, Ariano R, Iacovides H, Dodek P, Mirzanejad Y, et al.
Vancomycin pharmacodynamics and survival in patients with methicillin-resistant Staphylococcus aureus
-associated septic shock. Int J Antimicrob Agents 2013;41:255-60.
Rybak M, Lomaestro B, Rotschafer JC, Moellering R Jr., Craig W, Billeter M, et al.
Therapeutic monitoring of vancomycin in adult patients: A consensus review of the American society of health-system pharmacists, the infectious diseases society of America, and the society of infectious diseases pharmacists. Am J Health Syst Pharm 2009;66:82-98.
Murphy JE, Gillespie DE, Bateman CV. Predictability of vancomycin trough concentrations using seven approaches for estimating pharmacokinetic parameters. Am J Health Syst Pharm 2006;63:2365-70.
van Hal SJ, Paterson DL, Lodise TP. Systematic review and meta-analysis of vancomycin-induced nephrotoxicity associated with dosing schedules that maintain troughs between 15 and 20 milligrams per liter. Antimicrob Agents Chemother 2013;57:734-44.
Mohammedi I, Descloux E, Argaud L, Le Scanff J, Robert D. Loading dose of vancomycin in critically ill patients: 15 mg/kg is a better choice than 500 mg. Int J Antimicrob Agents 2006;27:259-62.
Wang G, Hindler JF, Ward KW, Bruckner DA. Increased vancomycin MICs for Staphylococcus aureus
clinical isolates from a university hospital during a 5-year period. J Clin Microbiol 2006;44:3883-6.
DiMondi VP, Rafferty K. Review of continuous-infusion vancomycin. Ann Pharmacother 2013;47:219-27.
Hanrahan T, Whitehouse T, Lipman J, Roberts JA. Vancomycin-associated nephrotoxicity: A meta-analysis of administration by continuous versus intermittent infusion. Int J Antimicrob Agents 2015;46:249-53.
Hao JJ, Chen H, Zhou JX. Continuous versus intermittent infusion of vancomycin in adult patients: A systematic review and meta-analysis. Int J Antimicrob Agents 2016;47:28-35.
Cataldo MA, Tacconelli E, Grilli E, Pea F, Petrosillo N. Continuous versus intermittent infusion of vancomycin for the treatment of gram-positive infections: Systematic review and meta-analysis. J Antimicrob Chemother 2012;67:17-24.
Schentag JJ. Clinical pharmacology of the fluoroquinolones: Studies in human dynamic/kinetic models. Clin Infect Dis 2000;31 Suppl 2:S40-4.
Forrest A, Nix DE, Ballow CH, Goss TF, Birmingham MC, Schentag JJ, et al.
Pharmacodynamics of intravenous ciprofloxacin in seriously ill patients. Antimicrob Agents Chemother 1993;37:1073-81.
Meinl B, Hyatt JM, Forrest A, Chodosh S, Schentag JJ. Pharmacokinetic/pharmacodynamic predictors of time to clinical resolution in patients with acute bacterial exacerbations of chronic bronchitis treated with a fluoroquinolone. Int J Antimicrob Agents 2000;16:273-80.
Zelenitsky SA, Ariano RE. Support for higher ciprofloxacin AUC 24/MIC targets in treating Enterobacteriaceae bloodstream infection. J Antimicrob Chemother 2010;65:1725-32.
Craig WA, Ebert SC. Killing and regrowth of bacteria in vitro
: A review. Scand J Infect Dis Suppl 1990;74:63-70.
Turnidge J. Pharmacodynamics and dosing of aminoglycosides. Infect Dis Clin North Am 2003;17:503-28, v.
Craig WA. Optimizing aminoglycoside use. Crit Care Clin 2011;27:107-21.
Barclay ML, Begg EJ. Aminoglycoside adaptive resistance: Importance for effective dosage regimens. Drugs 2001;61:713-21.
Mingeot-Leclercq MP, Tulkens PM. Aminoglycosides: Nephrotoxicity. Antimicrob Agents Chemother 1999;43:1003-12.
Schentag JJ, Cerra FB, Plaut ME. Clinical and pharmacokinetic characteristics of aminoglycoside nephrotoxicity in 201 critically ill patients. Antimicrob Agents Chemother 1982;21:721-6.
Mattie H, Craig WA, Pechère JC. Determinants of efficacy and toxicity of aminoglycosides. J Antimicrob Chemother 1989;24:281-93.
Gilbert DN. Once-daily aminoglycoside therapy. Antimicrob Agents Chemother 1991;35:399-405.
Munckhof WJ, Grayson ML, Turnidge JD. A meta-analysis of studies on the safety and efficacy of aminoglycosides given either once daily or as divided doses. J Antimicrob Chemother 1996;37:645-63.
Stankowicz MS, Ibrahim J, Brown DL. Once-daily aminoglycoside dosing: An update on current literature. Am J Health Syst Pharm 2015;72:1357-64.
van Lent-Evers NA, Mathôt RA, Geus WP, van Hout BA, Vinks AA. Impact of goal-oriented and model-based clinical pharmacokinetic dosing of aminoglycosides on clinical outcome: A cost-effectiveness analysis. Ther Drug Monit 1999;21:63-73.
Aronoff GR, Berns JS, Brier ME, Golper TA, Morrison G, Singer I, et al
. Drug Prescribing in Renal Failure: Dosage Guidelines in Adults. Philadelphia: American College of Physicians; 1999.
O'Shea S, Duffull S, Johnson DW. Aminoglycosides in hemodialysis patients: Is the current practice of post dialysis dosing appropriate? Semin Dial 2009;22:225-30.
Udy AA, Roberts JA, Lipman J. Clinical implications of antibiotic pharmacokinetic principles in the critically ill. Intensive Care Med 2013;39:2070-82.
Blot S, Lipman J, Roberts DM, Roberts JA. The influence of acute kidney injury on antimicrobial dosing in critically ill patients: Are dose reductions always necessary? Diagn Microbiol Infect Dis 2014;79:77-84.
Eyler RF, Mueller BA, Medscape. Antibiotic dosing in critically ill patients with acute kidney injury. Nat Rev Nephrol 2011;7:226-35.
Li AM, Gomersall CD, Choi G, Tian Q, Joynt GM, Lipman J, et al.
Asystematic review of antibiotic dosing regimens for septic patients receiving continuous renal replacement therapy: Do current studies supply sufficient data? J Antimicrob Chemother 2009;64:929-37.
Heintz BH, Matzke GR, Dager WE. Antimicrobial dosing concepts and recommendations for critically ill adult patients receiving continuous renal replacement therapy or intermittent hemodialysis. Pharmacotherapy 2009;29:562-77.
Parker SL, Sime FB, Roberts JA. Optimizing dosing of antibiotics in critically ill patients. Curr Opin Infect Dis 2015;28:497-504.
Roberts JA, Lipman J. Antibacterial dosing in intensive care: Pharmacokinetics, degree of disease and pharmacodynamics of sepsis. Clin Pharmacokinet 2006;45:755-73.
Han PY, Duffull SB, Kirkpatrick CM, Green B. Dosing in obesity: A simple solution to a big problem. Clin Pharmacol Ther 2007;82:505-8.
Hites M, Taccone FS. Optimization of antibiotic therapy in the obese, critically ill patient. Réanimation 2015;24:278-94.
Wurtz R, Itokazu G, Rodvold K. Antimicrobial dosing in obese patients. Clin Infect Dis 1997;25:112-8.
Payne KD, Hall RG 2nd
. Dosing of antibacterial agents in obese adults: Does one size fit all? Expert Rev Anti Infect Ther 2014;12:829-54.