Use of Pharmacokinetics and Pharmacodynamics to Optimize Antimicrobial Treatment Pseudomonas aeruginosa

SUPPLEMENT ARTICLE
Use of Pharmacokinetics and Pharmacodynamics
to Optimize Antimicrobial Treatment
of Pseudomonas aeruginosa Infections
David S. Burgess
College of Pharmacy, University of Texas at Austin, Austin, and Departments of Pharmacology and Medicine, University of Texas Health Science
Center at San Antonio, San Antonio
From the time that the first antibiotics were developed,
determining the appropriate drug regimen has been
challenging and, at times, somewhat controversial. Fortunately, with greater understanding of antimicrobial
pharmacodynamics, rational approaches for determining optimal dosing regimens can be pursued to ensure
use of the most effective regimen to achieve a successful
clinical outcome. Using pharmacokinetic (PK)/pharmacodynamic (PD) relationships to optimize therapy
could be critical when treating difficult infections, particularly infections caused by Pseudomonas aeruginosa.
This organism possesses a selectively permeable outer
membrane, along with several efflux pump mechanisms, that confer intrinsic resistance to multiple antimicrobial classes [1–3]. Antimicrobial treatment of P.
Reprints or correspondence: Dr. David S. Burgess, Clinical Pharmacy Programs,
MSC 6220, University of Texas Health Science Center, 7703 Floyd Curl Dr., San
Antonio, TX 78229-3900 ([email protected]).
Clinical Infectious Diseases 2005; 40:S99–104
2005 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2005/4004S2-0003$15.00
aeruginosa infections commonly results in the development of resistance. Because of the difficulty and severity of treating these infections, numerous studies
have investigated the most effective strategies for treating P. aeruginosa infections. The present article will
review the necessary PK/PD requirements for effective
treatment of P. aeruginosa infections, along with the
therapeutic options commonly used today.
PK/PD CONSIDERATIONS
The antimicrobial classes commonly used to treat P.
aeruginosa infections include the b-lactams (including
penicillins, cephalosporins, monobactams, and carbapenems), aminoglycosides, and fluoroquinolones. These
agents can be classified according to whether they engage in concentration-independent (or time-dependent) or concentration-dependent killing. By use of a
combination of in vitro studies, animal models, and
clinical data, PD targets have been determined that correlate with a successful outcome for a particular antimicrobial regimen [4–7].
Optimal PK/PD for P. aeruginosa Infections • CID 2005:40 (Suppl 2) • S99
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The study of pharmacodynamics has greatly enhanced our understanding of antimicrobials and has enabled
us to optimize dosing regimens. Applying this knowledge to the clinical setting can be critical for the treatment
of Pseudomonas aeruginosa infections. Because of its selectively permeable outer membrane and multiple efflux
pump mechanisms, P. aeruginosa has high intrinsic resistance to many available antimicrobials. Numerous
studies have established pharmacodynamic values for concentration-dependent agents (maximum serum concentration:minimum inhibitory concentration [MIC] and area under the serum concentration–time curve:
MIC) and concentration-independent agents (i.e., percentage of time that the drug concentration remains
greater than the MIC) that help predict the probability of a successful outcome. Current therapies attempt to
meet these target values. However, to reduce the risk of clinical failures, combination therapy (typically, a blactam with an aminoglycoside or fluoroquinolone) is commonly used to enhance eradication rates and decrease
the risk of developing resistance. Although combination therapy ensures a greater chance of selection of
appropriate treatment, timely initial administration of antimicrobial therapy remains a key factor for reducing
the likelihood of death for these patients.
Table 1.
for b-lactam therapy, various strategies can be used to optimize
dosing of these agents to achieve maximum bactericidal effect.
Some strategies involve using more-frequent daily doses, administering the dose through continuous infusion, or using
concomitant inhibitors of antimicrobial clearance. Several PK
studies have shown that continuous infusion will increase the
probability of achieving PD targets for the b-lactams [8–10].
However, the results of clinical studies comparing continuous
infusion with intermittent dosing have been inconclusive. In
fact, a well-designed, randomized, controlled study has yet to
be performed to differentiate between the 2 dosing regimens.
Clearly, more in vitro and clinical data are needed to determine
the optimal %t 1 MIC value for treating P. aeruginosa infections
and to distinguish which dosing strategy will optimize outcomes for patients treated with b-lactams.
Concentration-dependent agents. Unlike the b-lactams, the
PD parameter maximum serum concentration (Cmax):MIC is
used to assess the effectiveness of concentration-dependent
agents. The higher the concentration achieved, the faster the rate
of bacterial killing. Typically, a Cmax :MIC ratio of 8–10 has been
associated with effective treatment of and prevention of resistance
in gram-negative and -positive bacteria [11, 12]. For this reason,
optimal dosing strategies for these agents should attempt to
achieve as high a peak value as possible. If the Cmax :MIC target
value cannot be achieved, then the area under the serum concentration–time curve (AUC):MIC value may provide an additional parameter with which to judge a drug’s effectiveness.
The aminoglycosides have been used for 150 years, but only
recently has dosing of this antimicrobial class been optimized
for the most effective bacterial killing. Several in vitro and in
vivo animal studies have shown the concentration-dependent
nature of this class of antibiotics for gram-negative infections
[11, 13]. Early studies with netilmicin revealed that a Cmax :MIC
ratio of 8 was required to prevent regrowth of P. aeruginosa
[11]. In general, a Cmax :MIC ratio of 8–10 has been accepted
as achieving a maximum bactericidal effect against gram-negative pathogens, although few studies have looked specifically
at P. aeruginosa (table 2) [12].
The concentration-dependent nature of the aminoglycosides
has been observed in animal models [4, 13]. In a neutropenic
murine infection model, the AUC showed the greatest corre-
b-Lactam pharmacodynamic (PD) target values for effective treatment of Pseudomonas aeruginosa infection.
Antimicrobial agent [reference]
PD target value
Source model
Ticarcillin [4]
%t 1 MIC, 100%
Neutropenic mouse thigh infection
Cefotaxime, ceftriaxone, ceftazidime,
and cefpirome [5]
%t 1 MIC, 35%; static %t 1 MIC, 60%–70%
(to prevent regrowth)
Neutropenic mouse thigh and lung infections
Ceftazidime [6]
Cefepime [7]
Maintain concentration 6.6⫻ the MIC
%t 1 MIC, 14.3⫻ the MIC (83%–95%)
In vitro time-kill analysis
NOTE.
%t 1 MIC, percentage of time the drug concentration remains greater than the MIC.
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Human
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Concentration-independent (time-dependent) agents. The
bactericidal activity of the b-lactams is concentration independent. For these agents, maximum bacterial killing occurs at
concentrations 3–4 times the MIC, with further increases in
the drug concentration having little effect [5]. The effectiveness
of these agents correlates with the percentage of time that the
drug concentration remains greater than the MIC (%t 1 MIC)
[5]. Review of the literature reveals that the target value for
%t 1 MIC can vary depending on the agent and the particular
model used in the study (table 1).
An early study by Vogelman et al. [4] showed a direct relationship between the %t 1 MIC and the efficacy of a b-lactam
against P. aeruginosa infections. Using a neutropenic mouse
model, investigators found that maximum efficacy of ticarcillin
against P. aeruginosa required a %t 1 MIC value of nearly 100%.
A later study by Craig [5] attempted to correlate the antibacterial activity of the cephalosporins with the %t 1 MIC value by use of a neutropenic murine thigh- and lung-infection
model. For gram-negative bacteria, the %t 1 MIC value required for a static effect was 35%–40%. However, the maximum
bactericidal effect was achieved when the %t 1 MIC value approached 60%–70%.
Although maintaining the b-lactam concentration greater
than the MIC correlates with efficacy in vivo, some evidence
suggests that simply exceeding the MIC does not maximize the
antibacterial activity of these agents. By use of time-kill studies performed with various drug concentration:MIC ratios, a
concentration of 6.6 times the MIC was determined to provide maximum bactericidal activity of ceftazidime against P.
aeruginosa [6]. These results were further supported by a clinical study involving 36 patients with gram-negative infections
treated with cefepime [7]. For those patients, microbiological
success correlated best with the proportion of the dosing interval that cefepime concentrations exceeded 4.3 times the MIC.
To achieve 80% microbiological success, cefepime concentrations would have to be 14.3 times the MIC for 83% of the
dosing interval. However, some limitations of that study included the fact that only 20 of the 36 patients had positive
culture results, and those patients with a positive culture result
received adjunctive aminoglycoside therapy.
Since %t 1 MIC is widely accepted as an outcome parameter
Table 2.
Aminoglycoside pharmacodynamic (PD) target values for effective treatment of Pseudomonas aeruginosa infection.
Antimicrobial agent [reference]
Netilmicin [11]
Tobramycin [4]
Gentamicin, tobramycin, and amikacin [14]
Gentamicin, tobramycin, and amikacin [15]
NOTE.
PD target value
Source model
Cmax :MIC1 8
AUC 1 30
Cmax ⭓6 mg/mL for gentamicin and tobramycin;
Cmax ⭓24 mg/mL for amikacin
Cmax :MIC ⭓ 8
Neutropenic mouse thigh infection
Neutropenic mouse thigh infection
Human, gram-negative infections
Human, gram-negative infections
AUC, area under the serum concentration–time curve; Cmax, maximum serum concentration.
(with the exception of carbapenems), although they do exhibit
a PAE for gram-positive organisms. For the aminoglycosides,
studies have shown that, the higher the concentration of drug,
the longer the duration of the PAE.
The fluoroquinolones were the first class of drugs to use
extensive PD data to develop dosing regimens. Similar to the
findings for aminoglycosides, in vitro models showed that a
Cmax :MIC ratio of 10 was required for effective killing and
prevention of regrowth of resistant subpopulations. A second
parameter was the AUC:MIC ratio, for which a value of 100–
125 was recommended for gram-negative infections (although
a ratio of only 30–40 is required for gram-positive infections)
[20]. These results were further supported by animal studies
and clinical data (table 3). Using in vitro kill-curve analysis,
MacGowan et al. [23] demonstrated that levofloxacin and ciprofloxacin achieved similar bactericidal effects against 3 strains
of P. aeruginosa once the AUC:MIC ratio reached 125. Although ciprofloxacin tends to have MIC values 2-fold lower than those of levofloxacin for P. aeruginosa, levofloxacin
achieves plasma and tissue concentrations ⭓2 fold higher than
those of ciprofloxacin [20]. Both agents should then provide
similar activity against these infections in a patient.
Ciprofloxacin and levofloxacin are the only fluoroquinolones
commercially available that are approved by the Food and Drug
Administration for the treatment of systemic P. aeruginosa infections [24, 25]. As with the aminoglycosides, optimal treatment of P. aeruginosa infections with fluoroquinolones would
require achieving as high a concentration as clinically possible
Table 3. Fluoroquinolone pharmacodynamic (PD) target values for effective treatment of Pseudomonas aeruginosa infection.
Antimicrobial agent [reference]
PD target value
Enoxacin [11]
Ciprofloxacin and ofloxacin [42]
Cmax :MIC 18
AUC:MIC 1100
Lomefloxacin [21]
Ciprofloxacin [22]
Cmax :MIC 110
AUC:MIC 1100
Levofloxacin and ciprofloxacin [30]
AUC:MIC 1157
AUC:MIC ⭓125
Levofloxacin and ciprofloxacin [23]
Source model
IVPM
IVPM
Neutropenic rat model
Human, retrospective
Mouse, mathematical modeling
In vitro time-kill curves
NOTE. AUC, area under the serum concentration–time curve; Cmax, maximum serum concentration;
IVPM, in vitro pharmacokinetic model.
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lation with efficacy for treating gram-negative infections. Evidence from early clinical studies showed agreement with the
results from in vitro and animal models, establishing a relationship between serum levels of aminoglycoside and clinical
efficacy [14–16]. One study was able to correlate efficacy with
the ratio of the serum concentration of aminoglycoside to the
MIC of the pathogen [15]. On the basis of these data, improved
dosing regimens were investigated to achieve optimal clinical
efficacy with the aminoglycosides [17–19].
Traditional dosing of the aminoglycosides typically involved
administering a low dose of the agent 2–3 times/day [17]. With
the increasing PD evidence of optimal aminoglycoside target
values, new dosing strategies were explored to maximize the
concentration-dependent nature of these antimicrobials. Oncedaily dosing that uses higher amounts of the drug has been
explored and was found to achieve efficacy that was at least
comparable to that of traditional dosing regimens while reducing the risk of nephrotoxicity [18, 19]. Once-daily dosing
can also increase the cost-effectiveness of aminoglycoside therapy by reducing preparation and administration time.
An extended dosing interval is possible with the use of aminoglycosides because of the postantibiotic effect (PAE) of these
agents. The PAE is the suppression of bacterial growth after
limited exposure of the organisms to the antibiotic. A number
of factors can influence the duration of the PAE, including the
organism and its MIC, the duration of exposure, the concentration of the drug, and the potency of the agent. The b-lactams
do not show a significant PAE for gram-negative organisms
S102 • CID 2005:40 (Suppl 2) • Burgess
COMBINATION THERAPY
Recommended treatments for systemic P. aeruginosa infections
typically involve combination therapy, since it increases the
chance of effective initial therapy before receiving susceptibility
results. Combination therapy may minimize the risk of developing resistance and has the potential for synergistic activity.
For serious P. aeruginosa infections, combination therapy has
traditionally included an antipseudomonal b-lactam (such as
piperacillin, ceftazidime, cefepime, aztreonam, imipenem, or
meropenem) with an aminoglycoside or a fluoroquinolone.
Aminoglycosides have been shown to confer in vitro synergy
when combined with a b-lactam. However, the aminoglycosides
are also associated with a greater risk of adverse events, such
as nephrotoxicity and ototoxicity. The fluoroquinolones also
display synergy when combined with a b-lactam, although usually not to such a high degree as the aminoglycoside/b-lactam
combinations [33, 34]. In addition, the fluoroquinolones are
available in iv and oral doses, allowing for convenient switching
of therapy during the therapeutic course.
In vitro studies evaluating antimicrobial combinations.
In vitro synergy studies have produced wide ranges of results
regarding the frequency of synergy with b-lactam combinations
involving fluoroquinolones or aminoglycosides. The synergy
results are dependent on several methodological factors, such
as the method of synergy testing used (i.e., checkerboard or
time-kill analysis), the susceptibility patterns of the isolates, and
the concentrations of antimicrobials used. In general, time-kill
analysis demonstrates a higher degree of synergy than does
checkerboard analysis and has been better correlated with clinical outcome for P. aeruginosa infection [35]. Although standardized definitions of synergy exist for either checkerboard or
time-kill analyses, standardization for each analysis does not
exist. Earlier work from our laboratory using time-kill analysis showed that b-lactams combined with gentamicin resulted
in synergy at a frequency of 79% when tested against 12 P.
aeruginosa isolates [34]. Although this frequency was higher
Figure 1. Comparison of killing rates of gentamicin (䉱), levofloxacin
(), and ciprofloxacin () against Pseudomonas aeruginosa strain 99036. , Growth control.
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to attain the PD target value for a successful clinical outcome.
A high-dose regimen of each of these drugs has been approved
for severe infections. The high-dose ciprofloxacin regimen increases the frequency of dosing (400 mg iv t.i.d., compared
with the traditional regimen of 400 mg iv b.i.d.), which increases the AUC from 12.7 mg ⫻ h/mL to 32.9 mg ⫻ h/mL, but
does not increase the Cmax (4.56 vs. 4.07 mg/mL for the b.i.d.
vs. t.i.d. dosing regimens, respectively) [24]. Higher doses (1400
mg) of ciprofloxacin are not recommended, because a potential
increased incidence of adverse events involving the CNS has
been associated with increased plasma concentrations of this
agent [26, 27]. For levofloxacin, a high-dose regimen of 750
mg q.d. results in approximately double the AUC (108 mg ⫻
h/mL vs. 54.6 mg ⫻ h/mL) and Cmax (12.1 mg/mL vs. 6.4 mg/
mL) values, compared with those for the 500 mg q.d. dose [25].
The higher Cmax and AUC values increase the probability of
attaining the necessary PD target values for successful clinical
outcomes [28, 29]. Fortunately, the safety profile of the 750mg levofloxacin dose is similar to that of the lower dose, allowing maximum drug exposure with once-daily dosing [25].
A recent study used a mathematical model to predict the
probability of clinical success associated with the use of fluoroquinolone treatment for P. aeruginosa infections [30]. By use
of population pharmacodynamics, an AUC:MIC ratio of 157
was determined to be the target to limit amplification of resistant subpopulations of P. aeruginosa during an infection.
When Monte Carlo simulation and the MIC distribution of P.
aeruginosa from a surveillance study were used, the probability
that a 750-mg q.d. levofloxacin regimen would meet this target
was 61.2%, compared with 61.8% for a ciprofloxacin regimen
of 400 mg t.i.d. Although no difference exists between levofloxacin and ciprofloxacin in achieving this desired target of
an AUC:MIC ratio of 157, neither agent would be considered
adequate for use as monotherapy against this organism. Other
available fluoroquinolones would not achieve a higher rate because of higher MIC values and/or lower drug exposure, compared with levofloxacin and ciprofloxacin.
Finally, additional consideration must be given when choosing antimicrobial doses for seriously ill patients because of their
altered pharmacokinetics. These patients tend to have differences in drug clearance, volume distribution, and elimination
half-life than do healthy individuals, even when renal and hepatic functions appear to be normal. Rebuck et al. [31] showed
significant increases in Cmax and AUC values of critically ill
patients treated with levofloxacin, compared with those of
healthy volunteers. In general, drug exposures are higher in
critically ill and elderly patients, and they may improve the
probability of attaining necessary PK/PD targets for effective
antimicrobial therapy [32]. However, careful monitoring and
dose adjustment may be necessary to minimize the risk of adverse events.
500 and 750 mg of levofloxacin, respectively; for resistant isolates, the rates were 38% and 63% for combinations with 500
and 750 mg of levofloxacin, respectively) [37]. In a report included in this supplement, Lister [38] used an in vitro PK model
to show that a levofloxacin-imipenem combination effectively
eradicated 3 clinical isolates of P. aeruginosa, whereas monotherapy with either agent allowed regrowth and the development of resistance.
Because of the methodology issues of synergy testing as discussed, it remains difficult to determine whether in vitro results
correlated with clinical efficacy. To date, no large-scale, prospective randomized clinical trials have specifically compared
monotherapy with combination therapy or have compared different combination therapies for treating P. aeruginosa infections. Information has predominantly relied on retrospective
analysis or extraction of data from comparative clinical trials,
usually for the treatment of nosocomial pneumonia. Studies
have shown that the use of combination therapy ensures a
greater likelihood of selection of initial adequate treatment for
P. aeruginosa infections and results in significantly decreased
mortality [39–41]. For P. aeruginosa infections, adequate initial
combination therapy administered in a timely manner must be
emphasized to optimize the chance of clinical success and decrease the risk of emergence of resistance.
SUMMARY
Systemic P. aeruginosa infections remain among the most challenging conditions facing physicians, because of the organism’s
high intrinsic resistance and its ability to acquire adaptive resistance during a course of therapy. However, the probability
of a successful clinical outcome can be improved with a thorough understanding of the antibiotic PK/PD profile against this
organism. As the field of pharmacodynamics has expanded over
the years, dosing regimens have been optimized in vitro to capitalize on the concentration-dependent or -independent nature
of antimicrobials, ensuring maximum bacterial killing and reducing the risk of developing resistance. Certain combinations
of antimicrobials provide synergistic activity against P. aeruginosa, and, in limited studies, combination therapy increases
the likelihood of selection of initial adequate therapy for patients. Providing timely and adequate antimicrobial therapy has
proven to be critical to achieving successful clinical outcomes
for these difficult-to-treat infections.
Acknowledgments
Financial support. Abbott; AstraZeneca; Merck; Ortho-McNeil; Wyeth.
Potential conflicts of interest. D.S.B. is a consultant to Abbott, AstraZeneca, Aventis, Merck, Ortho-McNeil, and Wyeth and serves on the speakers’ bureaus of Abbott, AstraZeneca, Aventis, Merck, Ortho-McNeil, and
Wyeth.
Optimal PK/PD for P. aeruginosa Infections • CID 2005:40 (Suppl 2) • S103
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than that associated with b-lactams combined with ciprofloxacin (58%) or levofloxacin (67%), the difference was not significant. Furthermore, the weaker the antimicrobial agent is
against P. aeruginosa, the more likely and easier it becomes to
demonstrate synergy. For example, as displayed in figure 1, the
in vitro killing by gentamicin alone is less than that by levofloxacin alone, which is less than that by ciprofloxacin alone.
Therefore, on the basis of the standard definition of synergy
that a 2-log10 reduction is needed with the combination, compared with the most active agent alone at 24 h, one can clearly
see that, for this isolate of P. aeruginosa, synergy would be more
easily observed for gentamicin, followed by levofloxacin and
then ciprofloxacin. Hence, synergy may not provide the most
practical means for comparing the effectiveness of all antimicrobial combinations, particularly if one or both agents in a
combination exhibit a high degree of potency against a particular pathogen (and, thus, would have a low likelihood of measurable synergy).
Time-kill analyses evaluating bactericidal activity may provide an additional indication of how effectively certain combinations can eradicate a pathogen. One study compared the
bactericidal activity of piperacillin-tazobactam used in combination with either gentamicin or ciprofloxacin for 6 strains
of P. aeruginosa [36]. Although both combinations showed synergy for all 6 strains, the ciprofloxacin combination resulted in
a greater amount of bacterial killing after 24 h. In a study from
our laboratory comparing the bactericidal activity of levofloxacin, ciprofloxacin, and gentamicin used in combination with
piperacillin-tazobactam and cefepime against 12 strains of P.
aeruginosa [34], we found no difference between levofloxacin
and ciprofloxacin combinations in bactericidal activity at 24 h.
In fact, the fluoroquinolones were bactericidal at 24 h for 90%
of the combinations, whereas the aminoglycosides were bactericidal for 100% of the combinations. The fluoroquinolone
combinations maintained bactericidal killing for all but 2 isolates, which were nonsusceptible to the fluoroquinolones and
had an MIC ⭓64 mg/mL for piperacillin-tazobactam [34]. In
another study, we compared the bactericidal activity of 500 and
750 mg of levofloxacin in combination with ceftazidime, cefepime, piperacillin-tazobactam, imipenem, and tobramycin
against 12 strains of P. aeruginosa [37]. The bactericidal activity
was maintained more often with 750 mg than with 500 mg of
levofloxacin (94% vs. 83%). In fact, the bactericidal activity
was related to the susceptibility of the isolates to levofloxacin. For those isolates that were susceptible to levofloxacin, no
difference in bactericidal activity was noted for the 500- and
750-mg levofloxacin regimens. However, for levofloxacin-intermediate and -resistant isolates, the bactericidal activity was
different for the 2 dosing regimens, with the 750-mg regimen
providing greater bactericidal activity (for intermediate isolates,
synergy was observed in 75% and 100% of combinations with
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