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Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
Address correspondence to: Daniel Gonzalez, PharmD, PhD, Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, 2320 Kerr Hall, CB #7569, Chapel Hill, NC 27599-7569.
Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
An understanding of the pharmacokinetic (PK) and pharmacodynamic (PD) principles that determine response to antimicrobial therapy can provide the clinician with better-informed dosing regimens. Factors influential on antibiotic disposition and clinical outcome are presented, with a focus on the primary site of infection. Techniques to better understand antibiotic PK and optimize PD are acknowledged.
Methods
PubMed (inception–April 2016) was reviewed for relevant publications assessing antimicrobial exposures within different anatomic locations and clinical outcomes for various infection sites.
Findings
A limited literature base indicates variable penetration of antibiotics to different target sites of infection, with drug solubility and extent of protein binding providing significant PK influences in addition to the major clearing pathway of the agent. PD indices derived from in vitro studies and animal models determine the optimal magnitude and frequency of dosing regimens for patients. PK/PD modeling and simulation has been shown an efficient means of assessing these PD endpoints against a variety of PK determinants, clarifying the unique effects of infection site and patient characteristics to inform the adequacy of a given antibiotic regimen.
Implications
Appreciation of the PK properties of an antibiotic and its PD measure of efficacy can maximize the utility of these life-saving drugs. Unfortunately, clinical data remain limited for a number of infection site–antibiotic exposure relationships. Modeling and simulation can bridge preclinical and patient data for the prescription of optimal antibiotic dosing regimens, consistent with the tenets of personalized medicine.
Antibiotics are a key component of modern medicine, utilized in over half of all US hospitalizations, with >250 million additional treatment courses provided in the outpatient setting per year.
Along with other classes of anti-infectives, they represent a uniqueness in pharmacotherapy, where one patient's prescription can have a direct effect on others’, as antimicrobial utilization remains the primary driver of organism resistance.
the landscape of antimicrobial development has remained arid: no agents with novel mechanisms of action against resistant Gram-negative organisms are currently in late-stage clinical trials.
It is abundantly clear that optimization of antibiotic prescribing is necessary to preserve our current armamentarium. Although stewardship practices focusing on the restriction of use and shortening of treatment duration are well-cited,
Infectious Diseases Society of America and Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship.
further research on antibiotic pharmacokinetic (PK) and pharmacodynamic (PD) properties that maximize the probability of a successful outcome is needed.
The present review serves to provide the clinician with the principal PK/PD considerations for the most common antibiotics encountered in US hospital settings (β-lactams, vancomycin, fluoroquinolones, and aminoglycosides). The information contained herein can assist in producing dosing regimens that maximize clinical benefit while minimizing the risk of toxicity. While such concepts remain salient to antifungal and antiviral agents, these drugs are beyond the scope of this review. Particular emphasis is placed on the site of infection when applying these concepts to patient care. This review is by no means exhaustive, and the interested reader is encouraged to access the provided references and available textbooks
Nightingale C.H. Ambrose P.G. Drusano G.L. Murakawa T. Antimicrobial Pharmacodynamics in Theory and Clinical Practice. Vol 2nd ed. Taylor & Francis Group, LLC,
Boca Raton, FL2007
for a more in-depth discussion of antimicrobial PK/PD. Instead, the goal is to discuss the key principles related to rational selection of an antibiotic dosing regimen, which remain applicable to agents not discussed here in addition to new agents as they enter clinical practice.
Materials and Methods
PubMed (inception–April 2016) was searched for relevant publications using combinations of the search terms “antibiotic,” “penicillin,” “cephalosporin,” “carbapenem,” “vancomycin,” “fluoroquinolone,” “aminoglycoside,” “penetration,” “blood,” “bloodstream,” “lung,” “epithelial lining fluid,” “soft tissue,” “interstitial fluid,” “bone,” “central nervous system,” “cerebrospinal fluid,” “pharmacodynamic,” and “outcome.” Reference lists of identified publications were also reviewed for relevant articles.
Antimicrobial Pharmacokinetics
General Considerations
The kinetics of a drug refer to its rate of change as it traverses through a biological system, and is governed by the four essential processes of absorption, distribution, metabolism, and excretion. While antibiotic PK is often considered in terms of the body’s effect on the drug, the agent’s physicochemical properties must also be considered to predict its disposition. Chief among them is the relative solubility of the antimicrobial, which can have a significant impact on its volume of distribution (Vd) and thus may prove key in selecting agents expected to attain adequate penetration to the site of infection.
As albumin is the primary plasma-binding protein for the majority of antibiotics, its concentrations should be considered when implementing and adjusting dosing regimens, with highly protein bound agents being most affected.
Finally, the agent’s major route of elimination warrants appreciation, particularly in times of changing clinical condition where development of end-organ dysfunction or critical illness can greatly enhance (renal failure)
Exceptions: cefazolin (highly protein bound), ceftriaxone (highly protein bound), ertapenem (highly protein bound), nafcillin/oxacillin (highly protein bound, hepatically cleared).
Exceptions: cefazolin (highly protein bound), ceftriaxone (highly protein bound), ertapenem (highly protein bound), nafcillin/oxacillin (highly protein bound, hepatically cleared).
With these PK properties in mind, it becomes clear that the primary infection site is a crucial variable in considering whether sufficient antibiotic exposures are likely to be attained for a given agent and dosing regimen. Indeed, the differing physiology of anatomic sites where bacteria can reside often results in variable degrees of antibiotic penetration and thus concentration at the site where pharmacologic effect occurs.
The sections that follow examine the relationship between antibiotic PK and exposures in the blood, lung, soft tissue, bone, and central nervous system (CNS). Table II provides an outline of hypothetical dose changes based on antimicrobial PK properties and infection site.
Table IIInfection site, pharmacokinetic considerations, and adaptation of dosing regimen.
The bloodstream is perhaps the simplest infection site to consider, as it comprises the central compartment from which systemically administered drug distributes to the tissues. When treating a patient with bacteremia, the clinician must account for the likelihood of the proposed antibiotic agent—and, more importantly, its proposed dosing regimen—to maintain sufficient exposures within the blood to rapidly clear the organism because delays in appropriate therapy are associated with increased mortality.
Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal-directed therapy was initiated in the emergency department.
Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy.
Of course, the factors described here must also be reconciled with identification of the primary source of infection, optimizing antimicrobial therapy for that site in parallel with blood to prevent recrudescence and the possibility of antibiotic resistance.
In addition to the underlying pathology of sepsis resulting in significant fluid extravasation and a high probability of augmented renal clearance,
standard therapy bundles that include volume resuscitation and inotrope support are likely to further alter antibiotic PK, with hydrophilic, renally cleared agents (β-lactams, vancomycin, aminoglycosides) being most susceptible.
Indeed, recent data have suggested that currently prescribed doses of β-lactams are prone to underexposure in the critically ill, yielding a lower probability of achieving positive clinical outcomes.
Subtherapeutic initial β-lactam concentrations in select critically ill patients: association between augmented renal clearance and low trough drug concentrations.
In contrast, the lipophilic fluoroquinolones are minimally affected by changes in volume status, owing to their considerable permeability across membranes.
Although it could be inferred that the presence of augmented renal clearance would result in lower exposures of ciprofloxacin and levofloxacin, the evidence supporting this theory is, to date, lacking.
The presence of endocarditis necessitates the additional consideration of antibiotic penetration within the vegetation, as a high bacterial inoculum and production of biofilm can result in suboptimal concentrations and treatment failures.
Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association.
Predictors of clinical and microbiological treatment failure in patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia: a retrospective cohort study in a region with low MRSA prevalence.
Short-course gentamicin in combination with daptomycin or vancomycin against Staphylococcus aureus in an in vitro pharmacodynamic model with simulated endocardial vegetations.
although clinical evidence remains scarce for the agents under consideration here. Nevertheless, current clinical practice guidelines advocate the use of dosing regimens at the high end of the licensed dosing range (β-lactams) or measured therapeutic range (vancomycin) to optimize treatment outcomes.
Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association.
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.
The epithelial lining fluid (ELF) is considered the target site for the treatment of pneumonia caused by extracellular pathogens, representing an available matrix for the measurement of antibiotic concentrations.
While sparse, literature does exist describing ELF penetration of various antimicrobial agents in the clinical setting; the data provided here are focused on infected patients wherever possible.
β-lactams display a wide variability in ELF-to-plasma penetration ratio, ranging from 0.21 for ceftazidime
Steady-state and intrapulmonary concentrations of cefepime adminstered in continuous infusion in critically ill patients with severe nosocomial pneumonia.
Piperacillin represents perhaps the most-studied agent, with a reported ELF:plasma ratio of ~0.50 (with corresponding tazobactam values ranging from 0.65 to 1.21).
Steady-state plasma and intrapulmonary concentrations of piperacillin/tazobactam 4 g/0.5 g administered to critically ill patients with severe nosocomial pneumonia.
In the ceftolozane study of healthy volunteers, it is important to note the considerably lower degree of tazobactam penetration versus that observed in critically ill patients,
Steady-state plasma and intrapulmonary concentrations of piperacillin/tazobactam 4 g/0.5 g administered to critically ill patients with severe nosocomial pneumonia.
; indeed, this study reported a demonstrably lower value for piperacillin as well (0.26). Counterintuitively, the opposite is found when considering meropenem, with lower ELF:plasma ratios reported for severely ill patients (~0.25)
in healthy individuals report values of ~0.34, and 0.44, respectively. These findings indicate a relatively lower extent of ELF penetration for carbapenems versus penicillins in infected patients, whereas penetration ratios for cephalosporins remain highly variable. This finding, along with an inability to correlate penetration to extent of protein binding, emphasizes the need for careful consideration of agent and regimen selection when treating patients for pneumonia.
Pharmacokinetic-pharmacodynamic considerations in the design of hospital-acquired or ventilator- associated bacterial pneumonia studies: look before you leap!.
Unfortunately, data are lacking for other commonly used β-lactams such as cefazolin, ceftriaxone, and oxacillin/nafcillin.
Despite its high degree of utilization, the permeability of vancomycin into ELF has been severely understudied, with only a few reports to guide therapeutic decisions.
From this limited literature base, best estimates for ELF:plasma penetration range from ~0.18 to 0.50, with most investigators recommending higher doses to achieve sufficient lung exposures. In stark contrast, the lung penetration of ciprofloxacin, levofloxacin, and moxifloxacin has been extensively studied, with the high Vd of fluoroquinolones producing ELF:plasma ratios >1.
Bronchopulmonary pharmacokinetic and pharmacodynamic profiles of levofloxacin 750 mg once daily in adults undergoing treatment for acute exacerbation of chronic bronchitis.
For aminoglycosides, lung disposition appears more complex, with gentamicin and tobramycin ELF:plasma ratios <1 early in the dosing interval but >1 after 6 to 8 hours: this apparent PK hysteresis could be explained by the considerable hydrophilicity of these compounds, resulting in slow rates of movement across biological membranes.
It must be cautioned, however, that in none of these studies were exposures examined over an entire dosing interval; thus, the possibility of redistribution from ELF to plasma remains a significant and unresolved issue.
Soft Tissue
Much like ELF for the lung, the interstitial fluid (ISF) concentration of an antibiotic provides the most appropriate measurement of target site exposure for extracellular infections of the soft tissue.
A comprehensive review on the pharmacokinetics of antibiotics in interstitial fluid spaces in humans: implications on dosing and clinical pharmacokinetic monitoring.
Using microdialysis techniques, which consist of implanting a perfused semipermeable membrane into the desired tissue and measuring drug concentrations within the dialysate, the most robust quantification of unbound (free) antibiotic in the ISF can be achieved.
The physicochemical properties of the antibiotic and its degree of protein binding largely dictate the extent of soft tissue penetration, as the vascular endothelium remains highly permeable to these small molecules.
Importantly, the clinician must thus remain cognizant of the infected patient’s relative proportions of adipose and muscle, as lower exposures of some hydrophilic agents in the ISF of adipose relative to muscle tissue have been observed.
Furthermore, the expected increased Vd of lipophilic agents with increased adipose may result in suboptimal concentrations to treat these infections. Although the appreciable influence of obesity is beyond the scope of this review, general measures of body composition (eg, fat-free mass, percentage of ideal body weight) may be considered additional factors when determining suitable antibiotic dosing regimens for soft tissue infections.
The composition of bone is unique, consisting of a matrix of collagen and hydroxyapatite that often provides a protected site for bacteria, evading the effects of the immune system and many antibiotics.
With osteomyelitis being associated with a high relapse rate and protracted antibiotic courses, emphasis should be placed on optimization of dosing regimens and a better understanding of PK properties that can influence exposure at the target site.
Although the literature on this topic is again sparse, some overarching patterns can be discerned, albeit the majority of data have been derived from non-infected patients.
As may be expected based on discussions of previous infection sites, β-lactams display variable penetration into bone, with ratios compared to serum ranging from ~0.1 for oxacillin to ~1 for cefepime.
Higher doses would thus be necessary if mirroring drug exposures in the blood is desired. Fluoroquinolones, maintaining high Vd values secondary to their lipophilicity, achieve higher bone:serum ratios than β-lactams or vancomycin, ranging from ~0.35 (ciprofloxacin) to ~0.75 for levofloxacin.
While studies are lacking for aminoglycosides, their high degree of hydrophilicity would be hypothesized to severely limit the penetration of these agents across the bone matrix.
Central Nervous System
The combination of tight junctions and active transport systems that form the blood–brain barrier create a substantial impediment to the penetration of most antibiotics into the cerebrospinal fluid (CSF).
As such, here perhaps more than any other infection site are the agents' PK properties determinant of attaining sufficient pharmacologic exposures. Also of critical impact is the presence of inflammation within the meninges, as this significantly alters the permeability of the blood–brain barrier, profoundly increasing CSF exposures for the majority of antibiotics.
Degree of lipophilicity appears the most influential characteristic associated with an antibiotic’s CSF penetration, as this property affords passive diffusion across the otherwise impervious cerebral membranes.
Lipophilicity at pH 7.4 and molecular size govern the entry of the free serum fraction of drugs into the cerebrospinal fluid in humans with uninflamed meninges.
Cerebrospinal fluid penetration and pharmacokinetics of vancomycin administered by continuous infusion to mechanically ventilated patients in an intensive care unit.
in intact meninges. With inflammation, however, the tight junctions that connect cerebral endothelial cells become more porous, allowing up to an order of magnitude higher CSF penetration for hydrophilic compounds.
Cerebrospinal fluid penetration and pharmacokinetics of vancomycin administered by continuous infusion to mechanically ventilated patients in an intensive care unit.
Levels of vancomycin in cerebrospinal fluid of adult patients receiving adjunctive corticosteroids to treat pneumococcal meningitis : a prospective multicenter observational study.
This knowledge must be reconciled clinically with the frequent use of corticosteroids to decrease meningeal inflammation, which in addition to blunting the immune system’s response to infection can decrease the CSF exposure of first-line agents; thus, larger doses are likely necessary to ensure antimicrobial success, consistent with guideline recommendations.
Levels of vancomycin in cerebrospinal fluid of adult patients receiving adjunctive corticosteroids to treat pneumococcal meningitis : a prospective multicenter observational study.
As would be expected, the effect of inflammation on CSF penetration is attenuated with fluoroquinolones, although enhancements have been reported in a limited number of patients.
Collectively, these findings make it clear that target site penetration is an important factor for reconciling PK differences between and within antibiotic classes, and interpreting published literature on antimicrobial effect. It is also apparent that the study of antibiotic exposures at the site of infection is deficient, with much of the evidence base from trials conducted decades ago, hindered by suboptimal experimental designs, limited numbers of observations, and outdated methods. Importantly, while published studies often observe infection site concentrations above the minimum inhibitory concentrations (MICs) of common pathogens despite various barriers to entry, as presented in the following section, these PK snapshots are ill-suited for drawing definitive conclusions on the adequacy of a given antibiotic regimen.
Antimicrobial Pharmacodynamics
Guiding Principles
The MIC represents the most elemental PD measure for antibiotics; however, this value simply reflects the potency of the given agent, providing no information regarding the time course of antimicrobial effect nor whether the rate of bacterial killing may be altered by changing drug exposure.
Far more informative is the incorporation of PK information to assess the ability of a given antibiotic and its chosen dosing regimen to kill the infecting pathogen and predict clinical outcome. Three major PD indices—the percentage of time that free drug remains above the MIC over a 24-hour period (fT>MIC), the ratio of free drug area under the concentration-time curve (AUC) to MIC over a 24-hour period (fAUC:MIC), and the ratio of maximum concentration to MIC (Cmax:MIC)—sufficiently link the kinetics of antimicrobial disposition to efficacy.
An additional factor is the agent’s post-antibiotic effect (PAE), which quantifies the persistence of bacterial suppression after short exposure to the drug, thus adding to the overall duration of antimicrobial effect.
Consideration of these metrics is essential in appropriately selecting and adjusting antibiotic regimens in clinical practice, and should be done in concordance with individual patient status and suspected site of infection. Representative PD properties and dosing characteristics for the antimicrobial classes discussed previously are provided in Table III. Although the field of antimicrobial PD was derived from in vitro and animal studies, for which a rich literature exists,
the focus here is on recent clinical applications and appraisals. Thus, alternative PD measures associated with the minimization of antimicrobial resistance such as the mutant prevention concentration are not discussed, as they at current have not been assessed in the clinic, though remain an important focus for future research.
Further, owing to less overall evidence supporting their use, alternative PD indices including measures related to percentage of time free drug remains above a low multiple of the MIC (eg fT>4 x MIC)
Cmax:MIC = ratio of maximum concentration to minimum inhibitory concentration (MIC); fAUC:MIC = ratio of free drug area under the concentration-time curve to MIC; fT>MIC = percentage of time free drug remains above the MIC; PAE = post-antibiotic effect.
β-lactams serve as the archetypal class of time-dependent antibiotics, whereby substantially increasing drug concentrations have minimal effects on the overall rate and extent of bacterial killing. Instead, maintaining a free drug concentration above the MIC of the organism for a portion of the dosing interval has been shown to best predict microbiologic efficacy.
The magnitude of this PD index varies according to β-lactam subclass, with typical fT>MIC values of ≥60% to 70% for cephalosporins, ≥50% for penicillins, and ≥40% for carbapenems providing maximal bactericidal effect.
Clinically, these PD targets have been evaluated in a surprisingly limited number of studies, with the majority focusing on antipseudomonal beta-lactams.
Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T>MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections.
For these agents, a broad range of fT>MIC values from >45% to 100% have been reported as necessary for achievement of favorable clinical or microbiologic outcomes, a likely consequence of heterogeneous patient populations, infecting organisms, and study designs. However, the most robust evidence remains in line with in vitro and animal estimates, with cefepime fT>MIC values >53% to 74% being associated with up to a 10-fold higher likelihood of favorable outcome.
Indeed, in a large study assessing the adequacy of contemporary β-lactam dosing regimens in critically ill patients, the inability to attain a fT>MIC >50% was associated with a 32% decreased likelihood of a positive clinical outcome.
Though likely not warranted in all patients, studies have shown average reductions in mortality of 33% to 50% when piperacillin/tazobactam and cefepime are dosed over 3 to 4 hours versus standard intermittent infusions (0.5–1 hour), with the largest benefits seen in critically ill patients and those with multidrug-resistant organisms.
Clinical outcomes with extended or continuous versus short-term intravenous infusion of carbapenems and piperacillin/tazobactam: a systematic review and meta-analysis.
Clinical outcomes with extended or continuous versus short-term intravenous infusion of carbapenems and piperacillin/tazobactam: a systematic review and meta-analysis.
though their use is likely to be reserved only for extreme cases secondary to logistical issues in maintaining dedicated intravascular access for administration. Despite the recent advances in our ability to derive optimized dosing regimens for β-lactam agents, studies linking PD target attainment and clinical outcomes are limited, an issue that must be reconciled to ensure that patients receive the best antimicrobial therapy based on infecting organism, infection site, and clinical status.
fAUC:MIC
Measures of free drug exposure over a 24-hour period (fAUC) in relation to the organism MIC are correlative with the antimicrobial efficacy for most antibiotic classes, with vancomycin and the fluoroquinolones having accrued the most data.
Importantly, this metric affords a fair amount of flexibility in selection of a dosing regimen, as simultaneously adjusting both the magnitude of the dose and the frequency with which it is administered will result in identical fAUC values. Consequently, this PD index incorporates components of both time (vancomycin) and concentration (fluoroquinolones) dependence in determining the rate and extent of bacterial killing.
Despite initial preclinical data showing maximal bacterial killing over a wide range of total drug AUC:MIC values for vancomycin, the threshold of ≥400 is ubiquitously used.
Early animal and in vitro studies indicate that total drug AUC:MIC values ≥30 to 100 are necessary to achieve maximum kill for fluoroquinolones, based on the infecting organism.
Correcting for protein binding of these respective agents produces equivalent fAUC:MIC values ≥200 for vancomycin and ≥21 to 70 for fluoroquinolones.
Secondary to the dramatic rise of methicillin-resistant Staphylococcus aureus (MRSA) over the past 2 decades, optimization of vancomycin therapy has garnered much attention in recent years. Although current practice guidelines recommend the measurement of trough concentrations as a surrogate of total drug AUC:MIC, this may yield overexposure in some patients and thus an increased risk of adverse effects.
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.
Systematic review and meta-analysis of vancomycin-induced nephrotoxicity associated with dosing schedules that maintain troughs between 15 and 20 milligrams per liter.
Evaluations of total drug AUC:MIC thresholds predictive of favorable outcomes have been conducted in various clinical settings, with results ranging from 211 in patients with complicated MRSA bacteremia and endocarditis to 578 in patients with septic shock due to MRSA; assuming 50% protein binding for vancomycin, equivalent fAUC:MIC values are ~106 to 289.
Impact of vancomycin exposure on outcomes in patients with methicillin-resistant Staphylococcus aureus bacteremia: support for consensus guidelines suggested targets.
Vancomycin AUC 24/MIC ratio in patients with complicated bacteremia and infective endocarditis due to methicillin-resistant Staphylococcus aureus and its association with attributable mortality during hospitalization.
Area under the concentration-time curve to minimum inhibitory concentration ratio as a predictor of vancomycin treatment outcome in methicillin-resistant Staphylococcus aureus bacteraemia.
Vancomycin AUC 24/MIC ratio in patients with complicated bacteremia and infective endocarditis due to methicillin-resistant Staphylococcus aureus and its association with attributable mortality during hospitalization.
emphasizing the need for careful selection of dosing regimens. Notably, recent data suggest that higher total drug AUC:MIC values within the first 48 hours of therapy may be most associated with clinical outcome, with thresholds upward of 600 (fAUC:MIC, ~300) being necessary.
Association between vancomycin day 1 exposure profile and outcomes among patients with methicillin-resistant Staphylococcus aureus infective endocarditis.
Unfortunately, achievement of such high vancomycin exposures is likely limited to the most sensitive of isolates, as large dosing requirements produce a high likelihood of toxicity.
In some of the first studies to assess PD indices and clinical outcomes, fluoroquinolone AUC:MIC values ≥125 for ciprofloxacin and ≥34 for levofloxacin were significantly associated with clinical and microbiologic cure.
Assuming ~30% protein binding for each, this outcome corresponds to fAUC:MIC values of ≥88 and ≥24, respectively, in line with preclinical estimates. Interestingly, later investigations
Relationship between fluoroquinolone area under the curve: minimum inhibitory concentration ratio and the probability of eradication of the infecting pathogen, in patients with nosocomial pneumonia.
reported the necessity of higher values to attain similar outcomes, which may be a consequence of infecting pathogen and severity of infection. In these studies, AUC:MIC values ≥250 for ciprofloxacin and ≥87 for levofloxacin were predictive of favorable outcome, corresponding to fAUC:MIC values of ≥175 and ≥61, respectively. Overall, the evidence shows a 2- to 28-fold higher probability of favorable outcome when these respective PD index values were reached.
Relationship between fluoroquinolone area under the curve: minimum inhibitory concentration ratio and the probability of eradication of the infecting pathogen, in patients with nosocomial pneumonia.
Here, maintaining concentrations above the organism MIC for an extended period of the dosing interval is unnecessary, and in fact discouraged, due to an increased risk of adverse effects.
As such, the focus here is on Cmax:MIC, which remains the clinically targeted metric and for which clinical outcomes data exist. In addition, there have been trials with fluoroquinolones that discern the influence of peak concentrations in their overall killing capacity.
Studies of gentamicin and tobramycin in patients being treated for sepsis and nosocomial pneumonia have established a Cmax:MIC ≥8 to 10 as the PD target associated with clinical response.
Impact of imipenem and amikacin pharmacokinetic/pharmacodynamic parameters on microbiological outcome of Gram-negative bacilli ventilator-associated pneumonia.
For endocarditis caused by Enterococcus species, current guidelines indicate that aminoglycosides are to be given as lower, multiple daily doses instead of the typical once-daily regimen, albeit the evidence to support such dosing is scant.
Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association.
Nevertheless, it may be anticipated that a measure of total drug exposure (ie, AUC:MIC) rather than Cmax:MIC would be a distinct correlate to efficacy for these patients, though such studies have yet to be conducted. While their PD index is often represented by fAUC:MIC, the concentration-dependent nature of bacterial killing by fluoroquinolones also results in Cmax:MIC as a predictive parameter for response.
Values of ≥8 for ciprofloxacin and ≥12.2 for levofloxacin were associated with significantly improved clinical and microbiologic outcomes, although as noted in the respective studies and supported by in vitro data, this index is likely most important when faced with an organism capable of rapidly developing resistance, such as Pseudomonas aeruginosa.
When considering antimicrobial dosing regimens, the selected agent’s PAE, in determining the overall duration of action, can have a significant influence. In general, all antibiotics exhibit some degree of PAE against susceptible Gram-positive organisms, with values ranging from <2 hours for β-lactams to nearly 5 hours for vancomycin against S. aureus, although point estimates vary considerably.
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 than components of the cell wall.
PAE values derived from animal models for these agents are on average between 2 and 6 hours (range, 1.2–12.8 hours for aminoglycosides; range, 1.9–7.5 hours for fluoroquinolones); 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 carbapenem subclass, whose agents have shown prolonged PAEs of ~2 to 4 hours against Enterobacteriaceae and P. aeruginosa, consistent with their lower fT>MIC requirement versus other β-lactams.
Control-related effective regrowth time and post-antibiotic effect of meropenem on gram-negative bacteria studied by bioluminescence and viable counts.
The relative paucity of clinical evidence confirming in vitro and animal model PK/PD observations speaks to the difficulty in conducting such trials, necessitating an integrative, efficient, and scientifically valid approach. In silico modeling of PK data and simulation of treatment course provides a powerful means of assessing the adequacy of current antimicrobial dosing regimens, and deriving those that optimize PD indices.
These techniques are being increasingly used both as a means of bringing new agents to market and for the evaluation of existing antimicrobial agents, minimizing industry risk on the one hand while maximizing clinical utility on the other.
Pharmacokinetic-pharmacodynamic considerations in the design of hospital-acquired or ventilator- associated bacterial pneumonia studies: look before you leap!.
Through the leveraging of PK/PD data from preclinical models of infection and application of advanced pharmacostatistical modeling, measures of exposure and response can be obtained for various pathogen-antibiotic-infection site combinations. By imputing patient-level data into these models and performing Monte Carlo simulations, which account for interindividual differences in PK parameters and antimicrobial susceptibility, predictions of PD target attainment are possible. This scenario has been shown for numerous agents, with optimal dosing regimens often inferred as those that eclipse the specified PD target (eg, a fT>MIC ≥50% or a fAUC/MIC ≥100) with a ≥90% probability.
Pharmacodynamic profiling of piperacillin in the presence of tazobactam in patients through the use of population pharmacokinetic models and Monte Carlo simulation.
Pharmacokinetic-pharmacodynamic target attainment analyses to evaluate in vitro susceptibility test interpretive criteria for ceftaroline against Staphylococcus aureus and Streptococcus pneumoniae.
Indeed, much of the aforementioned literature on antimicrobial penetration and efficacy has applied population PK modeling and Monte Carlo simulation to predict exposure–response relationships in patients and infer optimal dosing regimens for the clinical population being studied.
Any extrapolation of simulation results beyond the conditions used to develop the model should be done with caution, as differing pathogens, infection types, and illness severities are likely to yield differing rates of target attainment for a given drug and dosing regimen; ideally, studies for each combination of antimicrobial agent, infecting pathogen, and clinical scenario should be performed. In addition, such platforms can be used to study the effects of antibiotic resistance
Pharmacokinetics-pharmacodynamics of cefepime and piperacillin-tazobactam against Escherichia coli and Klebsiella pneumoniae strains producing extended-spectrum β-lactamases: report from the ARREST program.
Comparison of short versus prolonged infusion of standard dose of meropenem against carbapenemase-producing Klebsiella pneumoniae isolates in different patient groups: a pharmacokinetic–pharmacodynamic approach.
situations in which accruing an adequate number of patients in clinical trials is not feasible. Modeling and simulation can thus enhance the translation of preclinical in vitro and animal studies to clinical practice, informing trial design to optimize the results of future clinical studies in addition to being directly applicable to contemporary patient care.
Conclusions
Rising rates of antimicrobial resistance and a limited drug development pipeline underscore the need for preserving the utility of currently available agents. An appreciation of the PK/PD determinants of a given antibiotic can foster more rational and individualized dosing regimens, improving patient outcomes while simultaneously limiting the spread of resistance (Figure). Anticipating the extent of distribution to the site of infection is of primary importance for ensuring adequate drug exposures; however, significant knowledge gaps remain. To truly understand the pharmacology of antimicrobial agents, we must go beyond MICs, using metrics that account for the rate of bacterial killing and the effects different dosing regimens have on it. Use of PK/PD modeling and simulation can maximize the amount of clinically useful information derived from limited numbers of patients, thus guiding optimal therapy and fully aligning with the goals of personalized medicine.
FigureApproach to the infected patient for the provision of optimal antibiotic therapy.
The authors have indicated that they have no conflicts of interest regarding the content of this article. Dr. Gonzalez receives research support from Cempra, Inc (subaward to HHSO100201300009C) and Jacobus Pharmaceutical Company, Inc, for adult and pediatric drug development.
Acknowledgments
Dr. Gonzalez receives research support through 1K23HD083465-01 from the National Institute of Child Health and Human Development and from the nonprofit organization Thrasher Research Fund (www.thrasherresearch.org). Dr. Onufrak performed all literature retrieval and review, and wrote the manuscript. Drs. Forrest and Gonzalez reviewed the manuscript for accuracy and completeness.
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Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy.
Subtherapeutic initial β-lactam concentrations in select critically ill patients: association between augmented renal clearance and low trough drug concentrations.
Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association.
Predictors of clinical and microbiological treatment failure in patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia: a retrospective cohort study in a region with low MRSA prevalence.
Short-course gentamicin in combination with daptomycin or vancomycin against Staphylococcus aureus in an in vitro pharmacodynamic model with simulated endocardial vegetations.
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.
Steady-state and intrapulmonary concentrations of cefepime adminstered in continuous infusion in critically ill patients with severe nosocomial pneumonia.
Steady-state plasma and intrapulmonary concentrations of piperacillin/tazobactam 4 g/0.5 g administered to critically ill patients with severe nosocomial pneumonia.
Pharmacokinetic-pharmacodynamic considerations in the design of hospital-acquired or ventilator- associated bacterial pneumonia studies: look before you leap!.
Bronchopulmonary pharmacokinetic and pharmacodynamic profiles of levofloxacin 750 mg once daily in adults undergoing treatment for acute exacerbation of chronic bronchitis.
A comprehensive review on the pharmacokinetics of antibiotics in interstitial fluid spaces in humans: implications on dosing and clinical pharmacokinetic monitoring.
Lipophilicity at pH 7.4 and molecular size govern the entry of the free serum fraction of drugs into the cerebrospinal fluid in humans with uninflamed meninges.
Exceptions: cefazolin (highly protein bound), ceftriaxone (highly protein bound), ertapenem (highly protein bound), nafcillin/oxacillin (highly protein bound, hepatically cleared).
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