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Previous Article | Next Article 
Antimicrobial Agents and Chemotherapy, July 1998, p. 1837-1841, Vol. 42, No. 7
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Efficacy of Trovafloxacin, a New Quinolone Antibiotic, in
Experimental Staphylococcal Endocarditis Due to
Oxacillin-Resistant Strains
Arnold S.
Bayer,1,2,*
Cong
Li,1 and
Michael
Ing1,
Division of Infectious Diseases and the St.
John's Cardiovascular Research Center, Harbor-UCLA Medical Center,
Torrance, California 90509,1 and
the
UCLA School of Medicine, Los Angeles, California
900242
Received 17 February 1998/Returned for modification 30 March
1998/Accepted 6 May 1998
 |
ABSTRACT |
Therapeutic options for severe infections caused by strains of
oxacillin-resistant Staphylococcus aureus (ORSA) and
coagulase-negative staphylococci (ORSE) are very limited. With the
increasing resistance of such strains to aminoglycosides, rifampin, and
currently available quinolone agents, as well as the recent
documentation of increasing resistance of ORSA to vancomycin
(VANCO), new treatment alternatives are imperative. The in vivo
efficacy of trovafloxacin (TROVA), a new quinolone agent with excellent
antistaphylococcal activity in vitro, against experimental
endocarditis (IE) due to 
-lactamase-producing ORSA and ORSE strains
(ORSA and ORSE IE) was evaluated. TROVA (25 mg/kg of body weight
intravenously [i.v.] twice daily [b.i.d.]) was compared to VANCO
(20 mg/kg i.v. b.i.d.) and two regimens of ampicillin-sulbactam
(AMP-SUL; 200 mg/kg intramuscularly [i.m.] three times a day
[t.i.d.] and 20 mg/kg i.m. b.i.d.), with all agents given for 3 or 6 days. AMP-SUL was included as a comparative treatment regimen because
of its proven efficacy against experimental ORSA and ORSE IE. For both
ORSA and ORSE IE, TROVA, AMP-SUL, and VANCO each reduced
staphylococcal densities in vegetations compared to
untreated controls (P < 0.01). For ORSA IE, TROVA was
the most rapidly bactericidal agent
although not to a statistically
significant degreecorrelating with its superior bactericidal effect
in vitro compared to those of VANCO and AMP-SUL.
| |
INTRODUCTION |
The staphylococci are the most
common cause of nosocomial bloodstream infections worldwide, accounting
for more than 40% of such events according to most studies (28,
31). Moreover, the staphylococci are frequent causes of
community-acquired bacteremias, especially in certain patient
populations (e.g., persons with diabetes mellitus and intravenous drug
addicts) (19) and for certain infectious disease syndromes
(e.g., prosthetic valve endocarditis [IE], addict-related IE, and
hemodialysis vascular access site infections) (19). In
addition, the staphylococci cause a variety of other serious, localized
infections, such as wound infections, skin and soft-tissue abscesses,
and intra-abdominal and retroperitoneal abscesses (19).
Importantly, a substantial portion of cases of severe staphylococcal
infections, both nosocomial and community acquired, are now being
caused by strains which are resistant to the semisynthetic,
antistaphylococcal penicillins (i.e., oxacillin-resistant strains
(15, 25). Of note, many such strains of oxacillin-resistant Staphylococcus aureus (ORSA) and coagulase-negative
staphylococci (ORSE) have evolved multidrug-resistant phenotypes, being
variably resistant to selected aminoglycosides, rifampin, and/or
currently available quinolone agents (21, 27, 30). For
severe clinical infections caused by ORSA and ORSE strains, vancomycin
remains the most pivotal parenteral agent. Of particular concern is the recent documentation of significant clinical infections due to ORSA
strains with reduced susceptibility to vancomycin (VANCO) in vitro from
diverse geographic areas in the United States, as well as from Japan
(6, 7, 17). Use of vancomycin in such patients was
associated with persistent or relapsing infection; these observations
underscore the critical need for new antistaphylococcal antibiotics
with potent activity against ORSA and ORSE strains.
The current study was designed to examine the in vivo efficacy
against ORSA and ORSE of a new fluoroquinolone agent,
trovafloxacin (TROVA), which possesses potent and
broad-spectrum activity against both gram-negative and
gram-positive organisms (13, 26). We have previously
confirmed the in vivo efficacy of TROVA against experimental IE caused
by vancomycin-resistant enterococcal strains with both vanA
and vanB genotypes (2). The animal model examined (involving experimental IE) is a rigorous test of antimicrobial efficacy, featuring large in vivo inocula in cardiac vegetations (>106 to 107 CFU/g of tissue) (1, 3, 4,
18, 29).
(This study was presented in part at the 35th annual meeting of the
Infectious Diseases Society of America, San Francisco, Calif.,
September 1997 [abstr. 268]).
| |
MATERIALS AND METHODS |
Bacterial strains.
The staphylococcal strains used in this
investigation are clinical isolates which were kindly provided by
H. F. Chambers, San Francisco, Calif. These strains have been
characterized in detail elsewhere (8, 9). Strain 67-0 (wound
isolate) is a -lactamase-producing, heterotypic ORSA strain, which
is virulent in the animal IE model (18). SE 220 (blood
isolate) is a -lactamase-producing homotypic ORSE strain
(Staphylococcus haemolyticus) also used in previous animal
IE studies (8, 29). Both strains are ciprofloxacin susceptible (MIC [105-CFU inoculum] for both is 0.25 µg/ml).
Antibiotics.
VANCO and ampicillin (AMP) were purchased from
commercial sources. Sulbactam (SUL) and TROVA (as the prodrug
[alatrofloxacin] for intravenous [i.v.] administration) were
supplied by Pfizer Central Research (Groton, Conn.). For
alatrofloxacin, 1 mg is equivalent to ~0.80 mg of TROVA
(32). For in vitro testing, stock solutions of each agent
(1,000 µg/ml) were kept at 
70°C until thawed on the day of study.
For the in vitro studies, the parent compound, TROVA, was utilized. For
use in animal treatments, antibiotics were reconstituted according to
the manufacturers' recommendations just prior to in vivo
administrations.
Antibiotic susceptibility testing.
The MICs for the ORSA and
ORSE strains of the study antibiotics (VANCO, AMP, SUL, and TROVA) were
determined by a broth microdilution method (18, 29) in
cation-supplemented Mueller-Hinton broth (CSMHB) plus 2% NaCl at a
final inoculum of ~5 × 105 CFU/ml. MICs were read
after 24 h of incubation at 35°C as the lowest antibiotic
concentrations yielding no visible growth. The ability of SUL to
enhance the growth-inhibitory effects of AMP against the ORSA and ORSE
strains was also studied by using the same microtiter system. The
antibiotic concentration ranges for AMP and SUL were 0.125 to 128 and
0.062 to 64 µg/ml, respectively, to parallel the clinically available
formulation of this drug (Unasyn) which provides a 2:1 drug ratio
(18). Moreover, these microtiter antibiotic concentrations
encompass those achieved in the experimental IE model using the AMP-SUL
regimens in the current study (18, 29) (see below). An
enhanced growth-inhibitory effect was defined as at least a fourfold
decrease in the MIC of the AMP-SUL combination versus those of both
single agents. The MIC studies outlined above have been previously
reported for both the ORSA and ORSE strains (18, 29).
To determine the comparative in vitro bactericidal effects of AMP-SUL,
VANCO, and TROVA, time-kill curves were generated. A final inoculum of
~2 × 106 CFU of logarithmic-phase ORSA or ORSE
cells was incorporated into either antibiotic-free or
antibiotic-containing CSMHB (plus 2% NaCl). The final antibiotic
concentrations utilized for VANCO and TROVA represented twice the MIC
determined in the studies described above. For the AMP-SUL combination,
the concentrations of each drug used represented twice the MIC for each
agent determined in the combination drug microtiter study described
above. After 0, 6, and 24 h of incubation (35°C), 100 µl from
each growth tube was quantitatively cultured in CSMH agar plus 2% NaCl
for an additional 48 h, and surviving CFU were counted. A decline
in CFU per milliliter of 
3 log10 units after 24 h of
incubation (versus 0-h bacterial counts) was considered evidence of a
bactericidal effect (18, 29).
Animal model of IE.
The rabbit model of IE was used to
evaluate therapeutic efficacy in this study. New Zealand White rabbits
underwent carotid artery-to-left ventricle catheterization as
previously described (18, 29). Twenty-four hours later,
animals were challenged i.v. with the 95% infective dose inoculum for
each strain as previously determined (~5 × 106
CFU). Twenty-four hours postchallenge, blood cultures were performed to
document the induction of IE. Animals were then randomized to receive
either no therapy or their first antibiotic treatment. The number of
animals assigned to each treatment group was designed to achieve a
statistical power of 80% at the P 
0.05 level.
Serum antibiotic levels.
The pharmacokinetics of VANCO, AMP,
and SUL have been previously determined in this model of IE, and the
determination was not repeated in this study (5, 18). The
serum TROVA levels in infected animals with ORSA IE were determined. At
24 h postinfection, animals received either 10, 25, or 50 mg of
TROVA per kg of body weight (as the prodrug) by i.v. bolus. Serum
samples were obtained at 1, 2, 4, 6, and 24 h postdose for TROVA
level determination by the agar diffusion method performed with
antibiotic medium 11 (Difco Laboratories, Detroit, Mich.), with
Bacillus subtilis (ATCC 6633) as the indicator strain
(provided by Robert Polzer, Pfizer Central Research). The lower limit
of detection for this assay was 0.1 µg of TROVA per ml.
Antibiotic regimens.
Animals received either no therapy
(controls) or one of the following antibiotics: TROVA (25 mg/kg i.v.,
administered twice daily [b.i.d.] bid as the prodrug alatrofloxacin),
VANCO (20 mg/kg i.v., administered b.i.d.), or AMP (200 mg/kg
intramuscularly [i.m.], im, administered three times a day) plus SUL
(20 mg/kg i.m., administered b.i.d.). Therapy was continued for either
3 or 6 days. The VANCO and AMP-plus-SUL regimens were based on prior pharmacokinetic and experimental IE efficacy studies in this laboratory (5, 18, 29). Thus, the peak serum AMP levels achieved with the above dose are ~275 µg/ml (30 min postdose), with levels of ~60 µg/ml at 60 min postdose (18). Importantly, this AMP
regimen yields serum levels which exceed those concentrations known to effect an ~50% in vitro saturation of penicillin-binding protein (PBP) 2a, the low-affinity PBP which determines the ORSA and ORSE phenotype (5, 11, 15, 18). In addition, the SUL dose regimen
yields peak serum levels of >30 µg/ml (15 to 60 min postdose) (5), well exceeding the concentrations required for
bactericidal synergy with AMP against both the ORSA and ORSE strains
used in the present study. The TROVA regimen was based on both
pharmacokinetic studies in this laboratory (see below) and prior
studies of the efficacy of TROVA against experimental enterococcal IE
performed in this laboratory (2).
Evaluation of efficacy.
For the assessment of treatment
efficacy, all animals were sacrificed by i.v. sodium pentobarbital
overdosage at least 24 h after the last drug dose to minimize
antibiotic carryover effects in vivo. At the time of sacrifice, proper
catheter placement across the aortic valve was confirmed, and only
initially bacteremic animals with proper catheter placement and
macroscopic vegetations on the aortic valve were further analyzed. All
vegetations from a single animal were removed, weighed, homogenized,
serially diluted, and quantitatively cultured. The serial dilution
strategy further minimizes potential antibiotic carryover effects. For
calculation of the mean bacterial densities per gram of vegetation,
culture-negative vegetations were assigned a value based on vegetation
weight and the lower limit of detection of CFU-per-gram levels
(18, 29).
Statistical analyses.
The Fisher exact test was used for
comparing proportional data, while the Kruskal-Wallis analysis of
variance with correction for multiple comparisons was used for
comparing differences between staphylococcal densities in vegetation.
| |
RESULTS |
Antibiotic susceptibilities.
The MICs of the study antibiotics
for the ORSA and ORSE strains are shown in Table
1. As noted, both strains experienced synergistic growth inhibition by the combination of AMP and SUL, at
achievable levels in serum for both antibiotics in this experimental model (5, 18). Both staphylococcal strains were susceptible to VANCO as well as TROVA (FDA-approved MIC breakpoint = 2 µg/ml). MICs of TROVA and VANCO were four- and eightfold lower,
respectively, for the ORSE strain than for the ORSA strain.
For the ORSA strain, TROVA and AMP-SUL exerted rapid bactericidal
effects in vitro, with reductions in viable counts of 106
and 103.2 CFU/ml, respectively, by 6 h of incubation
(Fig. 1A). In contrast, VANCO exerted a
relatively slow bactericidal effect over the 24-h incubation period.
TROVA exerted a rapid bactericidal effect against the ORSE strain (Fig.
1B).
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|
FIG. 1.
Timed-kill curves of ORSA (A) and ORSE (B) strains. The
concentrations (in micrograms per milliliter) of the antibiotics used
(each is twice the MIC) are as follows: VANCO, 4; AMP, 16; SUL, 8; and
TROVA, 2 for ORSA strains; and VANCO, 0.5; AMP, 16; SUL, 8; and TROVA,
0.5 for ORSE strains.
|
|
Serum antibiotic levels.
The elimination half-life of TROVA
for the 25- and 50-mg/kg bolus doses was ~2 h (Table
2). Peak TROVA levels achieved by the 25- and 50-mg/kg i.v. bolus doses were observed at 1 h postdose and
exceeded the MICs for both the ORSA and ORSE strains by at least
twofold. In contrast the 10-mg/kg TROVA dose achieved peak serum levels
(at 1 h) that well exceeded the MIC for the ORSE strain but that
exceeded the MIC for the ORSA strain by less than twofold. Moreover,
the ratios of the area under the concentration-time curve to the MIC
for the 25- and 50-mg/kg i.v. bolus doses (but not for the 10-mg/kg
dose) were >7 for each study strain. Therefore, the 25 mg/kg dose was
chosen for this study.
Experimental IE.
For the ORSA strain, all three antibiotic
regimens were very active in terms of significant reductions of
intravegetation densities compared to untreated controls, after both 3 and 6 days of therapy. TROVA was the most rapidly bactericidal agent in
vivo, with ORSA densities in vegetation following 3 days of
therapy that were lower than those seen in animals receiving VANCO or AMP-SUL by ~102.25 and ~101.5 CFU/g,
respectively (Table 3). However, these
trends did not reach statistical significance. Relatively few
vegetations were rendered culture negative by the three antibiotic
regimens after 3 days of therapy. TROVA and AMP-SUL were the most
active agents at day 6 of therapy in terms of sterilizing vegetations
(63%), although this did not reach statistical significance compared to the VANCO regimen. (Table 3).
For the ORSE strain (Table 4), all three
antibiotic regimens were equally effective at significantly reducing
intravegetation staphylococcal densities after both 3 and 6 days of
therapy, compared to untreated controls. Similarly, all three
antibiotic regimens were equally effective in rendering most
vegetations culture negative after both 3 and 6 days of therapy (Table
4).
| |
DISCUSSION |
Over the past decade, the antimicrobial therapy of serious
staphylococcal infections (e.g., IE) has been extensively studied (10, 21, 23). The use of quinolone antibiotics for human IE
was addressed by several groups, predominantly in terms of providing a
potential oral treatment regimen for this serious infection. These
clinical trials documented the excellent efficacy of such
quinolone-based regimens (12, 16). However, over the past
decade, a number of important trends in antimicrobial resistance observed in both ORSA and ORSE strains have made the evaluation of
newer antimicrobial regimens for invasive staphylococcal infections mandatory. For example, in prosthetic valve IE, the vast majority of
cases are caused by ORSE strains (21). Moreover, increasing numbers of native valve IE cases are being caused by ORSA strains (24). In addition, many ORSA and ORSE strains exhibit
multidrug resistance, especially to the aminoglycosides. Of paramount
importance, despite the near-uniform susceptibility of ORSA and
ORSE strains to VANCO in vitro, numerous reports have
confirmed the often slow and suboptimal treatment outcomes by
using VANCO in single-drug or combination therapy regimens
(24). Lastly, the recent isolation of ORSA strains, from
broad geographic areas, with intermediate susceptibilities to VANCO
(MICs of 4 to 8 µg/ml) in patients failing VANCO-based regimens
(6, 7, 17) underscores the critical necessity for newer
antistaphylococcal therapies.
TROVA is a new fluoroquinolone agent with excellent and broad-spectrum
activity against both gram-positive and gram-negative organisms
(13, 26). A number of investigators have compared the in
vitro antibacterial activities of TROVA with those of other quinolones
and have confirmed that TROVA was significantly more potent than
standard, clinically available quinolones (e.g., ciprofloxacin) against many gram-positive organisms, including pneumococci,
group A streptococci, and quinolone-susceptible or
quinolone-resistant staphylococci (13, 26). In
addition, recent pharmacokinetic investigations of tissue (using
positron emission tomography) have documented the excellent penetration
of TROVA into most clinically relevant tissues, including the heart
tissue (14). Furthermore, recent studies of diverse
experimental animal models have provided in vivo evidence of the
clinical potential of TROVA against serious human infections
(2, 22). The current study was designed to evaluate
the therapeutic efficacy of TROVA against experimental IE due to both
ORSA and ORSE strains (ORSA and ORSE IE), in comparison to two regimens
which have proven effectiveness in this model (VANCO and AMP-SUL)
(18, 29).
The present investigation confirmed the excellent in vivo efficacy of
TROVA against both ORSA and ORSE experimental IE. Against ORSA IE,
TROVA was clearly the most rapidly bactericidal agent tested and was
the most active agent against the tested strain for rendering
vegetations culture negative over the 6-day treatment period (~50%
versus ~40% for AMP-SUL regimens and ~18% for VANCO regimens). These in vivo findings paralleled those showing the rapid
and complete killing of the ORSA strain in vitro within 6 h of
incubation with TROVA. Against ORSE IE, all three antibiotic regimens were quite active at reducing vegetation bacterial
densities over the 6-day treatment period. The observed superior
activity of VANCO against ORSE IE compared to its activity against ORSA IE undoubtedly reflects the eightfold-lower in vitro MIC of VANCO for
the ORSE strain than for the ORSA strain. Of note, against both ORSA
and ORSE IE, the AMP-SUL regimen was effective, confirming several
previous experiences with this combination against experimental staphylococcal IE (18, 29). Of interest, Kaatz et al.
(20) recently studied the efficacy of TROVA by using a
similar model of S. aureus IE caused by
oxacillin-susceptible and ORSA strains. Although the dose regimens of
TROVA and VANCO used were different from those in the present study and
although the duration of therapy selected was shorter than that
in the present study (4 versus 6 days), these investigators
documented microbiologic outcomes which parallel our own observations.
Thus, for the ORSA strain in their study, both TROVA and VANCO
were highly efficacious in eradicating ORSA from cardiac vegetations,
sterilizing nearly all lesions over the 4-day therapy course. These
high rates of vegetation sterilization for ORSA IE treated with
either TROVA or VANCO (100 and 98%, respectively) compared to
those from the present study (63 and 27%, respectively) may well
relate to the substantially lower MICs of both study drugs in the
former investigation. Accordingly, the TROVA and VANCO MICs for the
ORSA strain in the study of Kaatz et al. were 20-fold and 5-fold lower,
respectively, than the MICs for the ORSA strain utilized in the present
study. Moreover, the peak achievable levels of TROVA in serum seen in the previous study at 1 h postdose (20) were
substantially higher than those that we observed, despite a lower
overall TROVA dose. These differences in achievable levels in infected
rabbits in the two studies may well reflect intrinsic differences in
the virulences of the infecting strains between these investigations, and the subsequent impact of these differences on drug clearances.
In summary, TROVA exhibited excellent in vivo activity against
-lactamase-producing strains of ORSA and ORSE in a severe and
rigorous model of invasive staphylococcal infection. This agent thus
provides a potentially important advance in antimicrobial therapy, and
further clinical evaluation of this agent is justified. Moreover,
should this agent prove to be effective against ORSA strains with
reduced susceptibility to VANCO in vivo (6, 7, 17), it would
substantially broaden the therapeutic arsenal against
multidrug-resistant staphylococci.
| |
ACKNOWLEDGMENT |
This study was supported by a research grant from Pfizer
Pharmaceuticals, Inc., New York, N.Y.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Division of
Infectious Diseases, Harbor-UCLA Medical Center, 1000 West Carson St., Bldg. RB2/Room 225, Torrance, CA 90509. Phone: (310) 222-6422. Fax:
(310) 782-2016. E-mail: Bayer{at}HUMC.EDU.
Present address: Division of Infectious Diseases, Pettis VA Medical
Center, Loma Linda, CA 92357.
| |
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Abstract
Introduction
