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REVIEW ARTICLE
Year : 2017  |  Volume : 35  |  Issue : 3  |  Page : 340-346
 

Optimisation of antimicrobial dosing based on pharmacokinetic and pharmacodynamic principles


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 Publication12-Oct-2017

Correspondence Address:
Andrea Lay-Hoon Kwa
Department of Pharmacy, Singapore General Hospital, Outram Road 169 608
Singapore
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmm.IJMM_17_278

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 ~ Abstract 

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 2017 Oct 22];35:340-6. Available from: http://www.ijmm.org/text.asp?2017/35/3/340/216629



 ~ Introduction Top


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.[1] 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.[2],[3]

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.[4] 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 Top


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

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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.[5] 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.[5] 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).[5] A review on PK/PD for various sites of infection has been done.[5] 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).[6] 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.[3] Lipophilic antibiotics, on the other hand, are not greatly influenced by changes in fluid volume and may not require alterations in initial dosing.[3],[7],[8]
Table 1: Properties of commonly prescribed antimicrobials

Click here to view


As albumin is the primary plasma-binding protein for most antibiotics, its concentrations should be considered when implementing and adjusting dosing regimens.[9] 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.[9],[10] With low plasma albumin, there is an increase of the unbound drug. This is important as only the unbound drug can exert antimicrobial effects.[5] 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.[9]

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.[11] 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.[11] 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.[11] 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.[12],[13],[14]

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.[15]

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.[16] 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.[17],[18] Thus, longer intervals between doses are possible without compromising treatment efficacy.[16],[19] On the contrary, β-lactams maintain virtually no PAE against Gram-negative pathogens (≤1 hour), often requiring multiple daily doses to ensure adequate coverage.[16] An exception is the carbapenems, which have shown prolonged PAEs of ][2],[3],[4] hours against Gram-negative pathogens, consistent with their lower f T > MIC requirement compared to other β-lactams.[20],[21],[22]

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.[17] 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.[3] It capitalises on the PD properties of β-lactams to maximise bacterial killing, therefore potentially improving clinical outcomes.[23],[24] Several meta-analyses/reviews have been conducted to compare clinical benefits of prolonged (i.e., extended and continuous) infusion versus intermittent boluses.[25],[26],[27],[28],[29],[30],[31],[32],[33]

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.[34] Changing all patients from standard intermittent bolus dosing to extended or continuous infusion may not be warranted and may not confer any therapeutic advantage.[35] 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.[31] 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.[31],[34],[36]

β-lactam therapeutic drug monitoring (TDM) has not been widely investigated because of the wide therapeutic window associated with this class of antimicrobials.[37] 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.[4] 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.[4] 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.[4],[37]

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.[38]

Vancomycin

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.[5] A PK/PD target of AUC/MIC ≥400 has been advocated to achieve clinical improvement and microbiologic eradication of Staphylococcus aureus pneumonia and bacteraemia.[39],[40],[41] A 2- to 4-fold reductions in mortality were observed with attainment of these AUC/MIC thresholds.[42],[43],[44]

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.[45] 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.[46] 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.[45] 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.[45] Patients with initial troughs >20 mg/L were significantly more likely to experience nephrotoxicity during therapy compared with vancomycin troughs of ][15],[16],[17],[18],[19],[20]mg/L, although most vancomycin-induced nephrotoxicity were reversible and few required dialysis.[41],[47]

Doses of 15–20 mg/kg given every ][8],[9],[10],[11],[12] 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.[48],[49] 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).[45] 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.[50],[51],[52],[53] 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.[1],[2],[3],[4] 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.

Fluoroquinolones

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.[54] AUC/MIC ratio is the major PK/PD parameter determining efficacy and outcomes of fluoroquinolones, and targets range from 125–250.[54] AUC/MIC value of 125 or higher was associated with much higher rates of clinical and bacteriologic cure than values <125.[55] 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.[56] 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.[57]

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.[57]

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.[37] More clinical data on this topic are needed.

Aminoglycosides

Aminoglycosides are rapidly bactericidal and demonstrate concentration dependence, which means that bacterial killing is more profound with increasing f Cmax/MIC.[58] Optimal clinical efficacy in the treatment of Gram-negative infections occurs with a ratio ≥8–10.[59] 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).[60] 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.[61] 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.[62] As a result, the local renin-angiotensin system is activated, leading to local vasoconstriction and a decrease in the glomerular filtration rate.[62] The onset is often delayed till after 5 days of aminoglycoside therapy.[63] 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.[64] Once-daily dosing takes advantage of this and in addition provides a period where aminoglycosides could leach back into the lumen, reducing accumulation.[65]

Meta-analyses have shown either equivalence or superiority for once-daily dosing in clinical efficacy, bacteriologic efficacy and nephrotoxicity.[59] None has shown differences in auditory or vestibular toxicity or mortality rates.[59] 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.[66]

The recommended initial dose of amikacin is ][15],[16],[17],[18],[19],[20] 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.[59],[67]

Aminoglycoside TDM has been shown to significantly shorten hospitalisation, reduce nephrotoxicity and have a strong trend towards reduced mortality.[37],[59],[68] Sampling half an hour post-administration will approximate the peak levels which is affected by Vd and has a direct reflection on efficacy.[38] 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.[67] 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.[38] 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.[69] 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).[70] 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.[71],[72] A larger Vd contributes to a lower antibiotic serum concentration that may lead to suboptimal bacterial killing and potential treatment failure.[72] As such, hydrophilic antimicrobial agents frequently require a loading dose to achieve PK/PD targets rapidly.[72]

Drug clearance is altered by changes in haemodynamics. Hyperdynamic cardiac output may increase drug clearance, whereas renal or hepatic impairment may decrease drug clearance.[3] 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.[3] 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.[73],[74],[75]

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.[71],[76],[77]

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.[78] Antibiotic dosing in the obese patients has been reviewed elsewhere.[79],[80],[81]

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

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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2004 - Indian Journal of Medical Microbiology
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