The Anti-Infective Research Laboratory,
Department of Pharmacy Services, Detroit Receiving Hospital and
University Health Center,1 College of
Pharmacy and Allied Health Professions,2 and
School of Medicine,3 Wayne State
University, Detroit, Michigan 48201
Received 7 September 1999/Returned for modification 1 December
1999/Accepted 31 January 2000
 |
INTRODUCTION |
Infections due to
methicillin-resistant Staphylococcus aureus (MRSA) continue
to be a significant problem in the 1990s, especially since the
glycopeptide antibiotic vancomycin often is the only antimicrobial
agent available with reliable activity. The recent isolation of MRSA
with intermediate susceptibility (MICs, 8 µg/ml) to vancomycin
(vancomycin-intermediate S. aureus [VISA]) in both Japan
and the United States (8, 9, 10) indicates that MRSA soon
will become fully resistant to the last line of defense against this
virulent organism. The expression of decreased vancomycin susceptibility in staphylococci is heterogeneous (1,
18; J. M. Boyce, A. A. Medeiros, and K. Hiramatsu,
Abstr. 37th Intersci. Conf. Antimicrob. Agents Chemother., abstr.
LB-15, 1997; K. Hiramatsu, H. Hanaki, S. Boyle-Vavra, R. S. Daum,
H. Labischinski, and F. C. Tenover, Abstr. 37th Intersci.
Conf. Antimicrob. Agents Chemother., abstr. C-166, 1997) and
appears to be associated with thickened cell walls (25, 27,
29-31) and increased production of cell wall precursors
(29, 30). Interestingly, these strains express increased
quantities of penicillin binding proteins (PBPs) (17, 21)
and have improved susceptibility to methicillin (30).
The recent isolation of clinical strains of VISA emphasizes the
importance of developing novel antimicrobial regimens and/or agents for
future treatment considerations. Ampicillin-sulbactam could potentially
have activity against VISA isolates that express increased quantities
of PBPs. Trovafloxacin is a fluoroquinolone that has improved activity
against gram-positive organisms. The combination of these two drugs was
recently reported to improve activity against some strains of
vancomycin-resistant Enterococcus faecium (33).
We studied the activities of ampicillin-sulbactam and trovafloxacin
alone or in combination against three unique strains of VISA using a
one-compartment in vitro pharmacodynamic infection model.
| |
MATERIALS AND METHODS |
Bacterial strains.
The three VISA strains tested in this
investigation were 14379 (isolated from a dialysis patient with
peritonitis; William Beaumont Hospital, Royal Oak, Mich.) (J. Mitchell,
M. Ionescu, D. Farnaz, S. Donabedian, M. B. Perri, L. A. Thal, J. Sunstrum, J. W. Chow, T. Smith, and M. J. Zervos,
Abstr. 37th Intersci. Conf. Antimicrob. Agents Chemother., abstr.
LB-14, 1997), Mu50 (isolated from a pediatric patient with a surgical
wound infection; Juntendo Hospital, Tokyo, Japan) (18), and
992 (isolated from a patient in New Jersey with bacteremia; Centers for
Disease Control, Atlanta, Ga.) (9). A clinical strain of
heterogeneous MRSA (494) was used to compare the activities of the
tested antibiotics against VISA strains to that against a
vancomycin-sensitive strain.
In vitro susceptibility testing, antimicrobial agents, and test
media.
Ampicillin-sulbactam powder for injection (Unasyn; lot
T008A; Pfizer) and vancomycin (lot 35H040425; Sigma Chemical Company, St. Louis, Mo.) were commercially purchased. Trovafloxacin (Trovan; lot
25381-086-02) was supplied by Pfizer Pharmaceuticals. Mueller-Hinton broth (Difco Laboratories, Detroit, Mich.) supplemented with calcium (25 mg/liter) and magnesium (12.5 mg/liter) (SMHB) was used for broth
susceptibility testing and in all in vitro infection models. Tryptic
soy agar (TSA; Difco) plates were used to determine colony counts.
Microdilution MICs and minimal bactericidal concentrations (MBCs) of
vancomycin, trovafloxacin, and ampicillin-sulbactam were determined
with a standard inoculum of 5 × 105 CFU/ml according
to the guidelines of the National Committee for Clinical Laboratory
Standards (23).
In vitro pharmacodynamic infection model.
The in vitro
infection model consisted of a 250-ml one-compartment glass chamber
with ports for the addition and removal of SMHB, injection of
antibiotics, and removal of samples. Prior to each experiment, colonies
from overnight growth of bacteria on TSA were added to SMHB as
necessary to obtain a 108-CFU/ml suspension. A 2.5-ml
volume of this suspension was added to the infection chamber to produce
a starting inoculum of 106 CFU/ml. Fresh stock solutions of
trovafloxacin and ampicillin-sulbactam were prepared daily and were
stored at 2 to 8°C between dose administration times. Trovafloxacin
was administered every 24 h to simulate the expected peaks during
a 200- or a 400-mg intravenous dose (2.3 or 4.5 µg/ml, respectively)
(32). Ampicillin-sulbactam was administered to simulate the
peak concentrations obtained during a regimen of 3 g every 6 h (approximately 100 and 50 µg/ml, respectively) (14). A
dose of 400 mg every 24 h was simulated for trovafloxacin during
the combination regimens. Antibiotics were injected into the model over
30 s with a hypodermic syringe. A peristaltic pump (Masterflex;
Cole-Parmer Instrument Company, Chicago, Ill.) was used to displace
antibiotic-containing medium with fresh SMHB to simulate the half-life
of trovafloxacin (12 h) or ampicillin-sulbactam (1 h) (14,
32). A supplemental chamber was used during combination regimens
to delay the elimination of the longer-half-life drug (trovafloxacin)
from the infection chamber as previously described (5). The
glass model apparatus was placed in a water bath and maintained at
37°C for the entire 48-h study period. Each experimental regimen was
performed in duplicate in order to ensure reproducibility.
Pharmacodynamic analyses.
Samples (0.5 ml) were removed from
each infection model at 0, 0.5, 1, 2, 4, 6, 8, 24, 28, 30, 32, and
48 h. Each sample was serially diluted in cold 0.9% sodium
chloride, and bacterial counts were determined by placing 20-µl spots
of the appropriately diluted samples in triplicate on TSA and
incubating them at 37°C for 24 h. We determined these methods to
have a limit of detection of 2 log10 CFU/ml
(24). Antibiotic carryover was considered insignificant, since the peak concentrations of antibiotics were in the range of one
to four times the MICs for all tested strains. For all samples within
4 h of these peak concentrations, the viable log10 CFU
per milliliter was determined from at least the second 10-fold serial
dilution
the concentrations in these diluted samples ranged from 1/40
to 1/100 times the MIC. Average colony counts (log10 CFU
per milliliter) in the infection models were plotted against time to
generate time-kill curves. Duplicate values were averaged. The
reductions in the log10 CFU per milliliter over 48 h
were determined and compared between regimens. Bactericidal activity was defined as a 
3-log10 CFU/ml reduction from the
starting inoculum. Synergy and additivity between the antimicrobial
agents were defined as 2- and 
2-log10 CFU/ml reductions
in colony counts at 48 h compared to the results obtained with the
most active agent alone. The time to achieve 99.9% killing was
determined by linear regression (if R was 0.95) or by
visual inspection of the time-kill curves.
Pharmacokinetic analyses.
Samples (0.5 ml) from each
infection model were obtained at 0, 0.5, 1, 2, 4, 6, 8, 24, 28, 30, 32,
and 48 h for the determination of antibiotic concentrations. All
samples were stored at 
70°C until analysis (no later than 2 weeks
from the sampling date). Concentrations of trovafloxacin and
ampicillin-sulbactam were determined by a microbioassay with
Klebsiella pneumoniae ATCC 10031 and Bacillus
subtilis ATCC 6633 spore suspensions (Difco) as the indicator
organisms. For both ampicillin-sulbactam and trovafloxacin, blank
0.25-in. paper disks were spotted with 50 µl of samples or standards,
placed in triplicate on Mueller-Hinton agar plates preswabbed with a
0.5 McFarland suspension of organisms, and incubated for 18 to 24 h at 37°C. Correlation coefficients were >0.98 for both the
ampicillin-sulbactam and the trovafloxacin standard curves. The
coefficients of variation for the high (3-µg/ml) and low
(0.1-µg/ml) trovafloxacin standards were 4.5 and 6.7%, respectively.
The coefficients of variation for the high (100-µg/ml) and low
(5-µg/ml) ampicillin-sulbactam standards were 4.8 and 5.2%,
respectively. All antimicrobial pharmacokinetics were determined with
RStrip software (Micromath, Salt Lake City, Utah).
Statistical analyses.
The changes in the inoculum at 8 and
48 h were compared between regimens by use of analysis of variance
with Tukey's test for multiple comparisons. For all comparisons, a
P value of 0.05 indicated statistical significance. All
statistical analyses were performed with SPSS Statistical Software
(release 6.1.3; SPSS, Inc., Chicago, Ill.).
| |
RESULTS |
Susceptibility testing.
The MICs and MBCs for strains 14379, Mu50, 992, and 494 are summarized in Table
1. Strain 992 was the strain most
sensitive to ampicillin-sulbactam. For all VISA strains, the
trovafloxacin MICs were 1 µg/ml, and the trovafloxacin MIC for
strain 494 was 0.015 µg/ml.
In vitro infection models. (i) Pharmacokinetics.
The
mean ± standard deviation (SD) peak, trough, half-life, and
area under the curve from 0 to 24 h (AUC0-24) for
trovafloxacin (200 mg every 24 h) were 2.7 ± 0.3 µg/ml,
0.9 ± 0.3 µg/ml, 15.9 ± 4.9 h, and 38.1 ± 5.1 µg/ml/h, respectively. The mean ± SD peak, trough, half-life,
and AUC0-24 for trovafloxacin (400 mg every 24 h)
were 4.9 ± 0.3 µg/ml, 1.7 ± 0.1 µg/ml, 13.6 ± 0.7 h, and 67.2 ± 5.0 µg/ml/h, respectively. The mean ± SD peak, trough, half-life, and AUC0-24 for
ampicillin-sulbactam (administered every 6 h) were 103.8 ± 16.3 µg/ml, 2.5 ± 0.4 µg/ml, 0.98 ± 0.11 h, and
575.1 ± 100.2 µg/ml/h, respectively.
(ii) Trovafloxacin regimens.
The results for regimens in which
trovafloxacin was given every 24 h are shown in Table
2 and Fig.
1. Trovafloxacin produced rapid and
complete killing of strain 494 over the 48-h experiment. Trovafloxacin
at 200 mg every 24 h produced only slight killing of all three
VISA strains, and colony counts at 8 h were significantly higher
for strain Mu50 than for all the other strains. Regrowth occurred in
all VISA infection models by 24 h, and a blunted effect was
observed with the second doses. Trovafloxacin at 400 mg every 24 h
caused significantly lower colony counts for all VISA strains at both
the 8-h and the 48-h time points.
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FIG. 1.
Activities of trovafloxacin at 200 mg (A) or 400 mg (B)
administered every 24 h against VISA strains in the in vitro
infection model. Growth controls are represented by the corresponding
filled symbols for each strain. Error bars represent SDs.
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(iii) Ampicillin-sulbactam regimens.
The results for the
regimen in which ampicillin-sulbactam was given every 6 h are
summarized in Table 3 and Fig.
2. Ampicillin-sulbactam produced rapid
bactericidal activity against all four strains tested, and colony
counts at 8 h were at or below the limits of detection. This
regimen produced significantly lower colony counts for each organism at
both the 8-h and the 48-h time points compared with the trovafloxacin
(200 mg) regimen. Regrowth started at 24 h and continued at each
time point until 48 h for every strain except 992. The colony
counts of strain 992 were statistically lower between 24 and 48 h
than were those of all other organisms.
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FIG. 2.
Activity of ampicillin-sulbactam administered every
6 h against VISA strains in the in vitro infection model. Growth
controls are represented by the corresponding filled symbols for each
strain. Error bars represent SDs.
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(iv) Ampicillin-sulbactam-trovafloxacin combination regimens.
The results obtained for the combination models are summarized in Table
3 and Fig. 3. The combination of
ampicillin-sulbactam and trovafloxacin provided additional 2.7- and
0.7-log10 CFU/ml reductions in colony counts for strains
14379 and 992 but provided no additional activity compared to the most
active monotherapy regimen for strain Mu50 and the control strain
(strain 494).
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FIG. 3.
Activity of trovafloxacin at 400 mg administered every
24 h in combination with ampicillin-sulbactam every 6 h
against VISA strains in the in vitro infection model. Growth controls
are represented by the corresponding filled symbols for each strain.
Error bars represent SDs.
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| |
DISCUSSION |
The recent reports of MRSA with decreased vancomycin
susceptibility are a grim indication that therapeutic failures against these pathogens soon will be related to vancomycin resistance (8-10, 17, 18, 21). The mechanisms that produce and
regulate this decreased vancomycin susceptibility are incompletely
determined, but the presence of the enterococcal van gene
family has not been detected in VISA (Hiramatsu et al., 37th ICAAC;
Mitchell et al., 37th ICAAC). Increased production of cell wall
precursors, thickened and irregular cell walls, decreased autolysis,
increased quantities of PBPs, extracellular glycopeptide sequestration,
and slower growth all have been described (3, 4, 6, 12,
15-18, 20, 21, 25-27, 29-31; Boyce et al., 37th ICAAC;
Hiramatsu et al., 37th ICAAC; Mitchell et al., 37th ICAAC; R. F. Pfeltz, M. A. Batten, C. Baranyk, R. K. Jayaswal, and B. J. Wilkinson, Abstr. 98th Gen. Meet. Am. Soc. Microbiol., abstr. A-19,
1998). This glycopeptide resistance results in decreased susceptibility
to other glycopeptide antimicrobial agents, such as teicoplanin and LY333328 (1, 3, 27, 29, 30; J. R. Aeschlimann,
E. Hershberger, and M. J. Rybak, submitted for publication), so
alternate classes of antimicrobial agents will be necessary to treat
VISA infections. Trovafloxacin is a fluoroquinolone antimicrobial agent which has greatly improved activity against gram-positive pathogens (11, 28) and might have adequate activity against a VISA
isolate. As a threefold increase in the expression of PBPs 2 and 2' has been reported for Mu50 (17) as well as for in vitro
vancomycin-resistant staphylococcal mutants (21), we
hypothesized that the administration of higher doses of
ampicillin-sulbactam might also provide adequate anti-VISA activity,
since ampicillin has a good affinity for these PBPs (2).
The activity that we observed in the infection models for trovafloxacin
against VISA was predictably weaker than the activity against strain
494, based on the lower MIC for this strain, the known
concentration-dependent killing activity of fluoroquinolones, and the
pharmacodynamic predictors of activities for these agents (19). Although currently somewhat controversial, an
AUC0-24/MIC ratio of >100 appears to be necessary for
adequate fluoroquinolone activity against gram-positive bacteria. This
ratio was met only against the MRSA control strain (strain 494). Higher
doses of trovafloxacin did significantly increase VISA killing but
still did not provide bactericidal activity (as measured at 48 h).
Activity against all strains (quantified by the viable
log10 CFU per milliliter at 48 h) was significantly
correlated (R2, 0.76; P, <0.05) with
the log AUC0-24/MIC ratioa finding which agrees with the
findings of previous studies of fluoroquinolone activity against
S. aureus (13).
Ampicillin-sulbactam activity in the infection models was highest
against strain 992. The killing activity of the first
ampicillin-sulbactam dose was rapid against all VISA strains, and each
was killed to the limit of detection by 8 h, but regrowth did
occur between 24 and 48 h for all of the strains. It is unclear if
the regrowth that we observed in the infection models was due to the
emergence of resistance or if it simply reflected suboptimal antibiotic exposures. As noted, we did not observe changes in MICs. We and others
previously have observed this regrowth phenomenon (7, 22).
Regrowth in the in vitro infection models appears to occur most often
for antibiotics with time-dependent activity during pharmacokinetic
simulations, where concentrations either stay just above the MIC or
fall below the MIC during the course of dosing intervals. Indeed,
regrowth in our ampicillin-sulbactam infection models appeared to be
inversely related to the time (from 0 to 24 h) that concentrations
were above the MICs for the organisms (approximately 15, 11, 7, and
3 h for strains 992, 494, 14379, and Mu50, respectively).
Administration of ampicillin-sulbactam every 4 h or as a
continuous infusion could be a way to improve the time above the MIC to
decrease the degree of regrowth. This regrowth may be of questionable
significance, since the rapid initial clearance of the bacteria coupled
with a functioning immune system could be adequate enough to cure a
VISA infection. The successful treatment of such an infection with
ampicillin-sulbactam plus arbekacin (10) provides
encouraging support for this hypothesis.
In conclusion, we determined that trovafloxacin administered at 200 mg
every 24 h likely will not provide adequate activity against the
VISA strains isolated thus far. Trovafloxacin administered at 400 mg
every 24 h could improve activity. Ampicillin-sulbactam had good
initial activity against all three VISA strains, followed by bacterial
regrowth. The combination of these antimicrobial agents resulted in
some additive activity against two of the VISA strains and could
represent a viable treatment strategy. Although the therapeutic use of
trovafloxacin is now limited because of hepatotoxicity, the Food and
Drug Administration has advised physicians that its use should be
restricted to short-term treatment (<14 days) of "serious, life- or
limb-threatening infections...[when] the treating physician
believes that...the benefit of the product for the patient outweighs
the potential risk" (M. M. Lumpkin, Trovan health advisory;
http://www.fda.gov/cder/news/trovan/trovan-advisory.htm). Clearly,
an infection with VISA could fit these criteria.
We thank Elizabeth Coyle and Rhonda Atkins for assistance with the in
vitro infection models. We also thank Keichi Hiramatsu, Marcus Zervos,
and Fred Tenover for providing the strains of vancomycin-intermediate S. aureus.
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Activity of trovafloxacin (with or without ampicillin-sulbactam) against enterococci in an in vitro dynamic model of infection.
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Abstract
Introduction
Present address: School of Pharmacy, The University of Connecticut,
Storrs, CT 06269.
