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Antimicrobial Agents and Chemotherapy, September 2001, p. 2662-2665, Vol. 45, No. 9
The Clinical Microbiology Institute,
Wilsonville, Oregon 97070
Received 26 February 2001/Returned for modification 10 April
2001/Accepted 8 June 2001
Quinupristin-dalfopristin (Q-D) and eight other antimicrobial
agents were tested alone and in combination with Q-D in time-kill studies against 10 strains of macrolide-lincosamide-streptogramin B-resistant Staphylococcus aureus. Although Q-D is
normally a bactericidal drug, it was only bacteriostatic for these
isolates. Gentamicin alone was bactericidal against 7 of the 10 strains, and Q-D did not alter that killing effect. However, when
vancomycin, cefepime, ceftazidime, imipenem, piperacillin-tazobactam,
and ciprofloxacin were bactericidal when tested alone, the killing rates were reduced when combined with Q-D. The clinical significance of
this in vitro antagonism is unknown at this time, and more studies are needed.
Quinupristin-dalfopristin (Q-D) is a
new parenteral streptogramin combination that exhibits particular
antibacterial potency against gram-positive pathogens, including
methicillin-resistant Staphylococcus aureus (MRSA) strains
(1, 3, 9, 13, 14). The two components of Q-D, quinupristin
and dalfopristin, act synergistically and provide good activity against
macrolide-lincosamide-streptogramin B
(MLSB)-susceptible and -resistant strains of
S. aureus (4, 11). Although Q-D is bactericidal
against most staphylococci, it is bacteriostatic against only
constitutively MLSB-resistant strains
(8), and Q-D therapy of experimental endocarditis due to
such strains has failed (6, 7). Clindamycin resistance is
a surrogate indicator of a reduced bactericidal activity of Q-D against
staphylococci (8). How common is the clindamycin resistance phenotype? An international study of clinical isolates from
23 hospitals in 18 countries (2) documented clindamycin resistance among 42% of 462 MRSA isolates but only 3% of 1,003 methicillin-sensitive S. aureus (MSSA) isolates. In that
large survey, 99% of MSSA strains and 95% of MRSA strains were
reported to be susceptible to Q-D according to bacteriostatic
determinations: Q-D should have been bactericidal against 85% of the
1,465 S. aureus isolates because they were clindamycin susceptible.
Because bactericidal activity is considered important in the treatment
of certain infections, such as bacterial endocarditis, the use of Q-D
in treating such infections caused by
MLSB-resistant S. aureus is
problematic. The present study was designed to determine if Q-D may be
combined with other antimicrobial agents in order to ensure a
bactericidal effect against MLSB-resistant
S. aureus strains for which Q-D alone is not bactericidal.
For this study, we selected 10 strains of
MLSB-resistant isolates of S. aureus, including 8 MRSA and 2 MSSA strains, all of which had been previously demonstrated to have less than 99.9% killing during a 24-h exposure to
10 µg of Q-D/ml.
Time-kill studies were carried out following the principles defined by
the National Committee for Clinical Laboratory Standards (12). The following antimicrobial agents were tested at
one twofold concentration above their respective susceptible MIC
breakpoints: Q-D (2.0 µg/ml), vancomycin (8.0 µg/ml), cefepime (16 µg/ml), ceftazidime (16 µg/ml), imipenem (8.0 µg/ml),
piperacillin-tazobactam (8.0 and 4.0 µg/ml), ciprofloxacin (2.0 µg/ml), gentamicin (8.0 µg/ml), and rifampin (2.0 µg/ml). Each
drug was tested alone, and each of the latter eight drugs was tested in
combination with Q-D at the same concentration. One flask of inoculated
cation-adjusted Mueller-Hinton broth with no antibiotic served as a
control. Colony counts were performed on the control suspension at time
zero and on the control as well as each antibiotic-containing
suspension at 3, 6, 8, 12, and 24 h. Counts were performed in
duplicate, and the average of the two values was used. For this
presentation, only 24-h-colony counts are described; earlier
subcultures led to similar conclusions. Bactericidal activity was
defined as a The lack of bactericidal activity of Q-D against this set of S. aureus strains was confirmed (Table
1). During the 24-h test period,
gentamicin was bactericidal to seven isolates, and this activity was
not altered significantly when combined with Q-D (Fig.
1A). Vancomycin was bactericidal to five
strains, and when combined with Q-D, an antagonistic response was
observed with four of these strains (Table 1 and Fig. 1C). Kang and
Rybak (10) have demonstrated synergy between Q-D and
vancomycin in a time-kill study at much higher drug concentrations
against a strain of MRSA for which vancomycin alone was bactericidal
and Q-D was not.
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.9.2662-2665.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Interactions of Quinupristin-Dalfopristin with
Eight Other Antibiotics as Measured by Time-Kill Studies with 10 Strains of Staphylococcus aureus for Which
Quinupristin-Dalfopristin Alone Was Not Bactericidal
ABSTRACT
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3-log10 reduction in colony count
compared to the time zero count. Synergy or antagonism was defined as
2-log10 decrease or increase in colony counts
with a drug combination compared to the lower of the two colony counts
of the individual drugs alone.
TABLE 1.
Effects of eight antibiotics alone and with Q-D on
bacterial counts after 24-h exposure
View larger version (18K):
[in a new window]
FIG. 1.
Representative S. aureus time-kill
curves for treatment with gentamicin (8.0 µg/ml) alone and gentamicin
(8 µg/ml) plus Q-D (2.0 µg/ml) (A), ciprofloxacin (2.0 µg/ml)
alone and ciprofloxacin (2.0 µg/ml) plus Q-D (2.0 µg/ml) (B),
vancomycin (8.0 µg/ml) alone and vancomycin (8.0 µg/ml) plus Q-D
(2.0 µg/ml) (C), and imipenem (8.0 µg/ml) alone and imipenem (8.0 µg/ml) plus Q-D (2.0 µg/ml) (D).
The 
-lactam drugs were bactericidal for the two MSSA strains and one
MRSA strain, and this activity was inhibited when these drugs were
combined with Q-D (Fig. 1D). Ciprofloxacin showed bactericidal activity
against two strains, and antagonism was also observed with these two
strains when ciprofloxacin was combined with Q-D (Fig. 1B). Only one
instance of synergy was observed
Q-D plus rifampin against strain
SP1662, but this did not reach bactericidal levels (Table 1).
It is of interest that with the exception of gentamicin, nearly all drugs that achieved bactericidal activity when tested alone were inhibited when tested with Q-D. Since Q-D was bacteriostatic to these strains, all instances of antagonism occurred with a combination of a bacteriostatic drug with a bactericidal drug. This is consistent with other drug combinations for which antagonism has been observed (5). It must be emphasized, however, that antagonism in such in vitro tests does not necessarily translate into in vivo antagonism (5).
Vouillamoz et al. (15) tested Q-D and cefepime alone and
in combination at trough and peak serum levels by time-kill studies against MLSB-resistant MRSA strains. Neither drug
was bactericidal alone. At the trough levels (0.5 µg of Q-D/ml and
5.0 µg of cefepime/ml), there were 2-log10
reductions in counts at 24 h compared to the lower of the counts
achieved by each drug alone. But, at peak levels, a tendency toward
antagonism was observed. When experimental endocarditis caused by these
strains was treated with Q-D plus cefepime, a marked reduction in
vegetation bacterial counts was observed, but no reduction in counts
occurred in animals treated with either drug alone (15).
However, since neither drug alone was bactericidal for these organisms,
it does not resolve the question of whether the in vitro antagonism
observed when bactericidal drugs are combined with Q-D as a
bacteriostatic agent (MLSB-resistant staphylococci) will be a problem in the clinical setting.
Under the conditions of this study, Q-D inhibited the bactericidal
activity of vancomycin, ciprofloxacin, and four -lactam antibiotics
against MLSB-resistant S. aureus
cells. Further studies with experimental animals would be
helpful in determining whether this is strictly an in vitro phenomenon
or may have clinical consequences.
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ACKNOWLEDGMENTS |
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This study was made possible by a grant from Rhone-Poulenc Rorer Inc., now Aventis Pharmaceuticals.
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FOOTNOTES |
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* Corresponding author. Mailing address: The Clinical Microbiology Institute, 9725 SW Commerce Circle, Wilsonville, OR 97070. Phone: (503) 682-3232. Fax: (503) 682-2065. E-mail: cmi{at}hevanet.com.
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Antimicrobial Agents and Chemotherapy, September 2001, p. 2662-2665, Vol. 45, No. 9
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.9.2662-2665.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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