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Antimicrobial Agents and Chemotherapy, October 2000, p. 2880-2882, Vol. 44, No. 10
The Clinical Microbiology Institute,
Wilsonville, Oregon
Received 13 March 2000/Returned for modification 7 June
2000/Accepted 26 July 2000
Of 516 Staphylococcus aureus strains tested, 97.1%
were susceptible to quinupristin-dalfopristin, which was bactericidal
for 22 (56%) of the 39 strains tested, comparable to vancomycin. All 17 clindamycin and macrolide-resistant strains were inhibited but not
killed by quinupristin-dalfopristin, whereas all 22 clindamycin-susceptible strains (5 were macrolide resistant) were killed.
Quinupristin-dalfopristin is a
parenteral streptogramin composed of quinupristin (a streptogramin B
antibiotic) and dalfopristin (a streptogramin A antibiotic) in a 30:70
ratio (13). This combination has been shown to exhibit
synergistic in vitro antibacterial activity against staphylococci and
other gram-positive bacteria (17). Greater than 90% of
Staphylococcus aureus isolates have been reported to be
susceptible to quinupristin-dalfopristin at Quinupristin, dalfopristin, and quinupristin-dalfopristin were
provided by Rhone-Poulenc Rorer, Collegeville, Pa. Clindamycin, erythromycin, oxacillin, and vancomycin were procured from other commercial sources.
Broth microdilution tests (15) with 516 recent clinical
isolates of S. aureus compared the bacteriostatic activities
of quinupristin-dalfopristin, erythromycin, and clindamycin. The results are summarized in Table 1. Nearly
all S. aureus strains were susceptible to
quinupristin-dalfopristin, but macrolide resistance was not uncommon,
especially among methicillin-resistant S. aureus strains.
All strains were susceptible to vancomycin. From that series of 516 isolates, 39 strains were selected to provide roughly equal numbers of
strains susceptible and resistant to methicillin, erythromycin, and
clindamycin. These 39 strains were then tested by the broth
microdilution method for susceptibility to quinupristin and
dalfopristin alone, as well as quinupristin-dalfopristin, erythromycin,
clindamycin, vancomycin, and oxacillin (with 2% NaCl).
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Bactericidal Activity of Quinupristin-Dalfopristin
against Staphylococcus aureus: Clindamycin
Susceptibility as a Surrogate Indicator
ABSTRACT
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1.0 µg/ml (1, 3,
7, 10, 14, 17, 18), and this activity was not appreciably
affected by methicillin resistance (1, 3, 17, 18) or
quinolone resistance (1, 10). Although nearly all S. aureus strains are inhibited by quinupristin-dalfopristin, the
bactericidal activity of this drug is much more variable (3, 6,
9). Previous studies have shown that S. aureus strains that have cross-resistance to macrolides, lincosamides, and
streptogramin B antibiotics (MLSB) were not killed in vitro
by quinupristin-dalfopristin, nor did endocarditis in experimental
animals due to such strains respond to quinupristin-dalfopristin
therapy (5). Low quinupristin MICs were demonstrated to be
predictive of quinupristin-dalfopristin bactericidal activity against
staphylococci, and routine testing of quinupristin MICs was suggested
for this reason (5). Since adding quinupristin to routine
gram-positive susceptibility test panels would be a major step, it
would be of interest to know whether susceptibility to clindamycin or
erythromycin might be equally predictive of
quinupristin-dalfopristin bactericidal activity. Thus, the present
study was designed to determine the correlation between the
bactericidal activity of quinupristin-dalfopristin and the MICs of
quinupristin-dalfopristin, quinupristin, dalfopristin, erythromycin,
and clindamycin.
TABLE 1.
Susceptibility of 516 recent clinical S. aureus isolates to four antibiotics
Time-kill tests were performed with quinupristin-dalfopristin and
vancomycin (as the control drug) following the principles outlined by
the National Committee for Clinical Laboratory Standards (16). The drug concentrations used in these studies were 10 µg/ml for quinupristin-dalfopristin and 20 µg/ml for vancomycin. For both drugs, these concentrations were 10 to 40 times their MICs for
the organisms tested but were equivalent to readily achievable blood
levels with standard dosing (2, 4, 8). The initial inocula
were targeted to be 1.5 × 106 CFU/ml. Colony counts
were performed on the control suspension (no antibiotic) at time zero
and on the control and both antibiotic suspensions at 1, 3, 6, 8, and
12 h. A drug was considered bactericidal if it produced a
3-log10 reduction in colony counts during this incubation
period (99.9% killing).
Figure 1 provides examples of typical
time-kill curves achieved with quinupristin-dalfopristin and
vancomycin. When both drugs were bactericidal (Fig. 1A), the time
required to achieve 99.9% killing was generally 2 to 6 h
shorter for quinupristin-dalfopristin than for vancomycin. That is
consistent with the findings of Hoban et al. (9). Overall,
quinupristin-dalfopristin was bactericidal for 56% of our 39 selected
strains and vancomycin was bactericidal for 64% of these isolates.
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The MICs of dalfopristin ranged from 2.0 to 16 µg/ml, with 35 (90%)
of the dalfopristin MICs being 4.0 or 8.0 µg/ml. MICs of dalfopristin
could not predict the bactericidal activity of quinupristin-dalfopristin. However, quinupristin MICs did correlate well with clindamycin MICs and with the bactericidal activity of
quinupristin-dalfopristin (Table 2).
Quinupristin-dalfopristin was bactericidal for all
clindamycin-susceptible isolates, including the five that were
erythromycin resistant. Furthermore, none of the clindamycin-resistant
strains were killed by quinupristin-dalfopristin. With one exception,
isolates for which the quinupristin MICs were 16 µg/ml were
clindamycin susceptible and were killed by quinupristin-dalfopristin and those for which the quinupristin MICs were 32 µg/ml were not.
The one exception was a clindamycin-resistant isolate for which the
quinupristin MIC was 8.0 µg/ml that was not killed by quinupristin-dalfopristin. Although the quinupristin MICs were 16
µg/ml for all clindamycin-susceptible strains, the geometric mean
quinupristin MIC for those strains that were erythromycin resistant was
higher (8.0 µg/ml) than for those that were erythromycin susceptible
(3.0 µg/ml). However, quinupristin-dalfopristin was bactericidal for
both phenotypes.
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These data confirm the observation that MLSB-resistant strains of S. aureus are not killed by quinupristin-dalfopristin (5). Furthermore, the data strongly suggest that clindamycin susceptibility is a good surrogate indicator of quinupristin-dalfopristin in vitro bactericidal activity; MICs of quinupristin alone may also serve as a useful surrogate. Since clindamycin is a common component of gram-positive susceptibility test panels, it may provide useful information for the clinical laboratory in this regard. It should be noted, however, that there are multiple mechanisms of MLSB resistance among staphylococci (11), and these were not determined for the isolates studied here. The ermA gene is by far the most prevalent determinant of MLSB resistance in S. aureus (12), and it is reasonable to assume that the majority, if not all, of our MLSB-resistant strains resulted from this determinant. Whether other determinants of MLSB resistance would yield similar results remains to be determined.
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ACKNOWLEDGMENTS |
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This study was supported by a financial grant from Rhone-Poulenc Rorer, Collegeville, Pa.
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FOOTNOTES |
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* Corresponding author. Mailing address: The Clinical Microbiology Institute, 9725 SW Commerce Circle, Suite A-1, Wilsonville, OR 97070. Phone: (503) 682-3232. Fax: (503) 682-4548. E-mail: cmi{at}hevanet.com.
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Antimicrobial Agents and Chemotherapy, October 2000, p. 2880-2882, Vol. 44, No. 10
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Copyright © 2000, American Society for Microbiology. All rights reserved.
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