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RP 59500, a new streptogramin highly active against recent isolates of North American staphylococci
DIAGN MICROBIOL INFECT DIS 1993;16:223-226
223
NOTE
RP 59500, a New Streptogramin Highly Active Against Recent Isolates of North American Staphylococci Gordon L. Archer, Pierre Auger, Gary V. Doern, Mary Jane Ferraro, Peter C. Fuchs, James H. Jorgensen, Donald E. Low, Patrick R. Murray, L. Barth Reller, Charles W. Stratton, Christine B. Wennersten, and Robert C. Moellering, Jr.
To assess the potential clinical utility of RP 59500, 10 investigators from separate locations in the United States and Canada each tested -200 current isolates of staphylococci (Staphylococcus aureus and coagulase-negative staphylococci) by a
standard protocol. RP 59500 was highly active (MIC9o ~ 2 I~g/ml) against all strains, including those that were resistant to oxacillin, ciprofloxacin, erythromycin, and spiramycin.
RP 59500 is a new, semisynthetic streptogramin antimicrobial agent that can be administered parenterally and possesses excellent activity against a variety of Gram-positive bacteria. It has been developed from pristinamycin, which is a naturally occurring strep-
togramin that has b e e n isolated from Streptomyces pristinaespirales (Maskell and Williams, 1987). Pristinamycin consists of two major c o m p o n e n t s : pristinamycin IA and pristinamycin IIA. In combination, pristinamycin IA a n d pristinamycin IIA d e m o n s t r a t e a synergistic increase in activity in vitro against Staphylococcus aureus (Bouanchaud, 1992). Moreover, whereas individual c o m p o n e n t s are bacteriostatic, the combination often provides a bactericidal activity. Pristinamycin has s h o w n activity against a broad variety of strains of staphylococci, including organisms that are resistant to methicillin and macrolides such as e r y t h r o m y c i n (Maple et al., 1989). H o w e v e r , the v e r y low water solubility of the c o m p o n e n t s of pristinamycin has heretofore m a d e it impossible to develop a parenteral preparation. Recently, semisynthetic modification of the two major constituents of the antimicrobial has p r o v i d e d n e w derivatives that are w a t e r soluble and retain all of the biologic properties of the p a r e n t molecules. RP 59500 contains a mixture of derivatives of quinuclidinylthiomethyl-pristinamycin IA and diethy-
From the Medical College of Virginia (G.L.A.), Richmond, Virginia, USA; University of Massachusetts Medical Center (G.V.D.), Worcester, Massachusetts General Hospital (M.J.F.), Boston, and New England Deaconess Hospital (R.C.M., C.B.W.), Boston, Massachusetts, USA; St. Vincent's Hospital and Medical Center (P.C.F.), Portland, Oregon, USA; Medical Center Hospital (J.H.J.), San Antonio, Texas, USA; Mount Sinai Hospital (D.E.L.), Toronto, Ontario, Canada; Institut de Cardiologie de Montreal (P.A.), Montreal, Quebec, Canada; Barnes Hospital (P.R.M.), St. Louis, Missouri, USA; Vanderbilt University Medical Center (C.W.S.), Nashville, Tennessee, USA; and Duke University Medical Center (L.B.R.), Durham, North Carolina, USA. Address reprint requests to Dr. R.C. Moellering, Jr., Department of Medicine, New England Deaconess Hospital, Boston, MA 02215, USA. Received 6 October 1992; revised and accepted 3 November 1992. © 1993 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893/93/$6.00
224
G.L. Archer et al.
laminoethylsulfonyl-pristinamycin IIA (Barriere et al., 1992). Preliminary studies have shown that this antimicrobial agent has excellent in vitro activity against staphylococci (Aldridge et al., 1992; Fass, 1991), but there have been no studies of representative isolates from a broad geographic area of North America. This study was designed to determine the prevalence of RP 59500-resistant isolates of S. a u r e u s , S. e p i d e r m i d i s , and other coagulase-negative staphylococci in the hospital environment from a variety of geographically distinct locations in the United States and Canada. Approximately 150-200 recent unique isolates of S. a u r e u s and coagulase-negative staphylococci were obtained and tested by 10 investigators in 10 widely distributed, predominantly university medical centers in North America. All were recent clinical isolates, and the prevalence of methicillin-resistant strains among the organisms tested was chosen to be representative of the prevalence of methicillin resistance in each investigator's local environment. The organisms were identified using standard microbiologic techniques, and antimicrobial susceptibility was determined by the NCCLS standard agar dilution method [National Committee for Clinical Laboratory Standards (NCCLS), 1990]. Mueller-Hinton agar was used for all susceptibility tests, and incubation was carried out at 35°C for 20-24 h for all antimicrobial agents except oxacillin, which was incubated at 30°C. A series of reference strains [S. aureus ATCC 29213, S. a u r e u s 209 USA (oxacillin, erythTABLE 1
romycin, and spiramycin susceptible), S. a u r e u s 528 (oxacillin resistant and spiramycin susceptible), S. a u r e u s A676 (oxacillin, erythromycin, and spiramycin resistant)] was run with each batch. Antimicrobial agents used in these studies included RP 59500 and spiramycin (Rhone-Poulenc Rorer, Vitry. sur-Seine, France), erythromycin (Abbott Laboratories, North Chicago, IL), oxacillin (Bristol Laboratories, Evansville, IN), ciprofloxacin (Miles Laboratories, West Haven, CT), and vancomycin (Eli Lilly and Company, Indianapolis, IN). Susceptibility to the above organisms was determined against all isolates. In addition, some investigators also tested susceptibility of their strains to teicoplanin (MarionMerrell Dow Pharmaceuticals, Kansas City, MO) and daptomycin (Eli Lilly). The susceptibilities of North American staphylococci to RP 59500 and seven comparative agents are presented in Table 1. RP 59500 was the most active of the agents tested, followed by vancomycin, daptomycin, teicoplanin, and ciprofloxacin. There were no strains for which the MIC of RP 59500 exceeded 8 ~g/ml. The activity of RP 59500 was equally good against oxacillin-susceptible and oxacillin-resistant strains of staphylococci (Table 2). Likewise, RP 59500 exhibited excellent activity against erythromycin-resistant or ciprofloxacin-resistant staphylococci (Table 3). The fact that there was no crossresistance between RP 59500 and any other agents tested was confirmed by determining correlation coefficients between the minimum inhibitory con-
Susceptibility of North American Staphylococci to RP 59500 and Seven Comparative Agents MIC (~g/ml)
Organism (No. of Strains) S. aureus
(1045)
Coagulase-negative staphylococci (1021)
~265strains. b266strains. "199 strains.
Antimicrobial Agent
Range
50%
90%
RP 59500 Vancomycin Ciprofloxacin Spiramycin Erythromycin Oxacillin Teicop|anin a Daptomycinb
0.12-8 0.06-4 0.06->64 0.25->64 0.06-> 64 0.06->64 0.25-16 0.5-4
0.5 1 0.5 8 0.5 0.5 1 1
1
RP 59500 Vancomycin Ciprofloxacin Spiramycin Erythromycin Oxacillin Teicoplanin C Daptomycinc
0.03-8 0.03-4 0.03-> 64 0.03->64 0.03-> 64 0.03->64 0.25-32 0.25-4
0.5 1 0.25 8 64 1 2 1
1
2 >64 >64 >64 2 2 1 2 8 >64 >64 >64 16 4
Note
TABLE 2
225
Susceptibility of Oxacillin-Susceptible a n d Oxacillin-Resistant S t a p h y l o c o c c i to RP 59500 a n d Five O t h e r A g e n t s MIC (p.g/ml)
Organism (No. of Strains)
Antimicrobial Agent
Range
Oxacillin susceptible (895) a
RP 59500 Vancomycin Ciprofloxacin Spiramycin Erythromycin Oxacillin
0.12-8 0.06-2 0.06-> 64 0.25->64 0.06-> 64 0.06-2
Oxacillin resistant (150) b
RP 59500 Vancomycin Ciprofloxacin Spiramycin Erythromycin Oxacillin
0.25-4 0.25-4 0.12->65 4->65 0.12-> 64 4->64
Coagulase-negative staphylococci Oxacillin RP 59500 susceptible (621) a Vancomycin Ciprofloxacin Spiramycin Erythromycin Oxacillin
0.03-4 0.03-8 0.03->64 0.03->64 0.03-> 64 0.03-2
0.5 1 0.25 4 0.5 0.25
1 2 1 >64 >64 2
0.12-8 0.12-4 0.03-> 64 0.25->64 0.03->64 4->64
0.5 2 0.25 >64 >64 32
1 2 8 >64 >64 >64
50%
90%
S. aureus
OxaciUin resistant (400) b
RP 59500 Vancomycin Ciprofloxacin Spiramycin Erythromycin Oxacillin
0.5 1 0.5 8 0.5 0.5 1 1 2 >64 >64 >64
1 1 1 16 >64 0.5 2 2 32 >64 >64 >64
aOxacillin MIC of ~<2 ~g/ml. bOxacillin MIC of/>4 ~g/ml.
TABLE 3
Effect of Resistance to E r y t h r o m y c i n or Ciprofloxacin o n Susceptibility of S t a p h y l o c o c c i to RP 59500 MIC (p~g/ml) Resistance Pattern
Range
50%
90%
S. au~'eus
Erythro-R a Erythro-S b Cipro-R c Cipro-S a
0.12-4 0.12-2 0.25-4 0.12-8
1 0.5 1 0.5
2 1 2 1
CNS e
Erythro-R a Erythro-S b Cipro-R C Cipro-S a
0.12-8 0.03--4 0.12-4 0.03-8
0.5 0.5 0.5 0.5
1 1 1 1
Organism
~Erythromycin resistant (MIC > 4 ~g/ml). bErythromycin susceptible (MIC < 1 ~g/ml). ~Ciprofloxacin resistant (MIC > 2 t~g/ml). dCiprofloxacin resistant (MIC < 2 ~g/ml). eCoagulase-negative staphylococci.
G.L. Archer et al.
226
TABLE 4
Susceptibility of Various Species of Coagulase-Negative Staphylococci to RP 59500 MIC (p~g/ml)
Organism (No. Tested) S. S. S. S. S. S. S. S. S.
capitis (10) cohnii (2) epidermidis (295) hemolyticus (35) hominis (50) saprophyticus (29) sciuri (2) simulans (14) warneri (21)
Range
50%
90%
0.25-1 1-4 0.12-4 0.25-8 0.12-1 0.25-2 1-2 0.25-1 0.25-2
0.5 -0.5 1 0.5 1 -0.5 0.5
1 -0.5 2 0.5 2 -1 1
centrations (MICs) (numerical values) of RP 59500 and each of the other agents tested. None of these correlation coefficients was significant. Finally, RP 59500 s h o w e d excellent activity against a subset of coagulase-negative staphylococci which were identified to the species level (Table 4). Overall, only 11 of 2066 staphylococci in this entire study required >2 ~g/ml RP 59500 for inhibition of growth.
RP 59500 has been s h o w n to be highly active against S. aureus and coagulase-negative staphylococci isolated from a variety of geographically diverse locations in North America. Indeed, there were no strains in this s t u d y for which the MIC of RP 59500 was >8 ~g/ml. Moreover, all but 11 of the 2066 unique isolates tested in this s t u d y were inhibited by ~ 2 ~g/ml of RP 59500. At the present time, susceptibility break points for RP 59500 have not been determined, but peak serum levels as high as 24 ~g/ml have been obtained with doses of RP 59500 that were well tolerated in h u m a n subjects (Etienne et al., 1992). The activity of RP 59500 against both oxacillinresistant and oxacillin-susceptible staphylococci and against organisms resistant to erythromycin, spiramycin, and ciprofloxacin suggests that it has special potential for the treatment of infections due to resistant staphylococci, and it m a y provide a viable alternative to vancomycin in this setting. This study was supported by a grant-in-aid from Rhone-Poulenc Rorer, Vitry-sur-Seine, France. The advice of Dr. D.H. Bouanchaud in the design and execution of this study is gratefully acknowledged.
REFERENCES
Aldridge KE, Schiro DD, Varner LM (1992) In vitro antistaphylococcal activity and testing of RP 59500, a new streptogramin, by two methods. Antimicrob Agents Chemother 36:854-855. Barriere JC, Bouanchaud DH, Paris JM, Rolin O, Harris NV, Smith C (1992) Antimicrobial activity against Staphylococcus aureus of semisynthetic injectable streptogramins: RP 59500 and related compounds. J Antimicrob Chemother 30(Suppl A):1-8. Bouanchaud DH (1992) In-vitro and in-vivo synergic activity and fractional inhibitory concentration (FIC) of the components of a semisynthetic streptogramin, RP 59500. J Antimicrob Chemother 30(Suppl A):95-99. Etienne SD, Montay G, LeLiboux A, Frydman A, Garaud JJ (1992) A phase I, double-blind, placebo-controlled study of the tolerance and pharmacokinetic behaviour
of RP 59500. J Antimicrob Chemother 30(Suppl A):123131. Fass RJ (1991) In vitro activity of RP 59500, a semisynthetic injectable pristinamycin, against staphylococci, streptococci and enterococci. Antimicrob Agents Chemother 35:553-559. Maple PAC, Hamilton-Miller JMT, Brumfitt W (1989) Worldwide antibiotic resistance in methicillin-resistant Staphylococcus aureus. Lancet 1:537-539. Maskell JP, Williams JD (1987) In vitro susceptibility of oral streptococci to pristinamycin. J Antimicrob Chemother 19:585-590. National Committee for Clinical Laboratory Standards (NCCLS) (1990) Approved standard, M7-A2: methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, 2nd ed. Villanova, PA: NCCLS.
223
NOTE
RP 59500, a New Streptogramin Highly Active Against Recent Isolates of North American Staphylococci Gordon L. Archer, Pierre Auger, Gary V. Doern, Mary Jane Ferraro, Peter C. Fuchs, James H. Jorgensen, Donald E. Low, Patrick R. Murray, L. Barth Reller, Charles W. Stratton, Christine B. Wennersten, and Robert C. Moellering, Jr.
To assess the potential clinical utility of RP 59500, 10 investigators from separate locations in the United States and Canada each tested -200 current isolates of staphylococci (Staphylococcus aureus and coagulase-negative staphylococci) by a
standard protocol. RP 59500 was highly active (MIC9o ~ 2 I~g/ml) against all strains, including those that were resistant to oxacillin, ciprofloxacin, erythromycin, and spiramycin.
RP 59500 is a new, semisynthetic streptogramin antimicrobial agent that can be administered parenterally and possesses excellent activity against a variety of Gram-positive bacteria. It has been developed from pristinamycin, which is a naturally occurring strep-
togramin that has b e e n isolated from Streptomyces pristinaespirales (Maskell and Williams, 1987). Pristinamycin consists of two major c o m p o n e n t s : pristinamycin IA and pristinamycin IIA. In combination, pristinamycin IA a n d pristinamycin IIA d e m o n s t r a t e a synergistic increase in activity in vitro against Staphylococcus aureus (Bouanchaud, 1992). Moreover, whereas individual c o m p o n e n t s are bacteriostatic, the combination often provides a bactericidal activity. Pristinamycin has s h o w n activity against a broad variety of strains of staphylococci, including organisms that are resistant to methicillin and macrolides such as e r y t h r o m y c i n (Maple et al., 1989). H o w e v e r , the v e r y low water solubility of the c o m p o n e n t s of pristinamycin has heretofore m a d e it impossible to develop a parenteral preparation. Recently, semisynthetic modification of the two major constituents of the antimicrobial has p r o v i d e d n e w derivatives that are w a t e r soluble and retain all of the biologic properties of the p a r e n t molecules. RP 59500 contains a mixture of derivatives of quinuclidinylthiomethyl-pristinamycin IA and diethy-
From the Medical College of Virginia (G.L.A.), Richmond, Virginia, USA; University of Massachusetts Medical Center (G.V.D.), Worcester, Massachusetts General Hospital (M.J.F.), Boston, and New England Deaconess Hospital (R.C.M., C.B.W.), Boston, Massachusetts, USA; St. Vincent's Hospital and Medical Center (P.C.F.), Portland, Oregon, USA; Medical Center Hospital (J.H.J.), San Antonio, Texas, USA; Mount Sinai Hospital (D.E.L.), Toronto, Ontario, Canada; Institut de Cardiologie de Montreal (P.A.), Montreal, Quebec, Canada; Barnes Hospital (P.R.M.), St. Louis, Missouri, USA; Vanderbilt University Medical Center (C.W.S.), Nashville, Tennessee, USA; and Duke University Medical Center (L.B.R.), Durham, North Carolina, USA. Address reprint requests to Dr. R.C. Moellering, Jr., Department of Medicine, New England Deaconess Hospital, Boston, MA 02215, USA. Received 6 October 1992; revised and accepted 3 November 1992. © 1993 Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893/93/$6.00
224
G.L. Archer et al.
laminoethylsulfonyl-pristinamycin IIA (Barriere et al., 1992). Preliminary studies have shown that this antimicrobial agent has excellent in vitro activity against staphylococci (Aldridge et al., 1992; Fass, 1991), but there have been no studies of representative isolates from a broad geographic area of North America. This study was designed to determine the prevalence of RP 59500-resistant isolates of S. a u r e u s , S. e p i d e r m i d i s , and other coagulase-negative staphylococci in the hospital environment from a variety of geographically distinct locations in the United States and Canada. Approximately 150-200 recent unique isolates of S. a u r e u s and coagulase-negative staphylococci were obtained and tested by 10 investigators in 10 widely distributed, predominantly university medical centers in North America. All were recent clinical isolates, and the prevalence of methicillin-resistant strains among the organisms tested was chosen to be representative of the prevalence of methicillin resistance in each investigator's local environment. The organisms were identified using standard microbiologic techniques, and antimicrobial susceptibility was determined by the NCCLS standard agar dilution method [National Committee for Clinical Laboratory Standards (NCCLS), 1990]. Mueller-Hinton agar was used for all susceptibility tests, and incubation was carried out at 35°C for 20-24 h for all antimicrobial agents except oxacillin, which was incubated at 30°C. A series of reference strains [S. aureus ATCC 29213, S. a u r e u s 209 USA (oxacillin, erythTABLE 1
romycin, and spiramycin susceptible), S. a u r e u s 528 (oxacillin resistant and spiramycin susceptible), S. a u r e u s A676 (oxacillin, erythromycin, and spiramycin resistant)] was run with each batch. Antimicrobial agents used in these studies included RP 59500 and spiramycin (Rhone-Poulenc Rorer, Vitry. sur-Seine, France), erythromycin (Abbott Laboratories, North Chicago, IL), oxacillin (Bristol Laboratories, Evansville, IN), ciprofloxacin (Miles Laboratories, West Haven, CT), and vancomycin (Eli Lilly and Company, Indianapolis, IN). Susceptibility to the above organisms was determined against all isolates. In addition, some investigators also tested susceptibility of their strains to teicoplanin (MarionMerrell Dow Pharmaceuticals, Kansas City, MO) and daptomycin (Eli Lilly). The susceptibilities of North American staphylococci to RP 59500 and seven comparative agents are presented in Table 1. RP 59500 was the most active of the agents tested, followed by vancomycin, daptomycin, teicoplanin, and ciprofloxacin. There were no strains for which the MIC of RP 59500 exceeded 8 ~g/ml. The activity of RP 59500 was equally good against oxacillin-susceptible and oxacillin-resistant strains of staphylococci (Table 2). Likewise, RP 59500 exhibited excellent activity against erythromycin-resistant or ciprofloxacin-resistant staphylococci (Table 3). The fact that there was no crossresistance between RP 59500 and any other agents tested was confirmed by determining correlation coefficients between the minimum inhibitory con-
Susceptibility of North American Staphylococci to RP 59500 and Seven Comparative Agents MIC (~g/ml)
Organism (No. of Strains) S. aureus
(1045)
Coagulase-negative staphylococci (1021)
~265strains. b266strains. "199 strains.
Antimicrobial Agent
Range
50%
90%
RP 59500 Vancomycin Ciprofloxacin Spiramycin Erythromycin Oxacillin Teicop|anin a Daptomycinb
0.12-8 0.06-4 0.06->64 0.25->64 0.06-> 64 0.06->64 0.25-16 0.5-4
0.5 1 0.5 8 0.5 0.5 1 1
1
RP 59500 Vancomycin Ciprofloxacin Spiramycin Erythromycin Oxacillin Teicoplanin C Daptomycinc
0.03-8 0.03-4 0.03-> 64 0.03->64 0.03-> 64 0.03->64 0.25-32 0.25-4
0.5 1 0.25 8 64 1 2 1
1
2 >64 >64 >64 2 2 1 2 8 >64 >64 >64 16 4
Note
TABLE 2
225
Susceptibility of Oxacillin-Susceptible a n d Oxacillin-Resistant S t a p h y l o c o c c i to RP 59500 a n d Five O t h e r A g e n t s MIC (p.g/ml)
Organism (No. of Strains)
Antimicrobial Agent
Range
Oxacillin susceptible (895) a
RP 59500 Vancomycin Ciprofloxacin Spiramycin Erythromycin Oxacillin
0.12-8 0.06-2 0.06-> 64 0.25->64 0.06-> 64 0.06-2
Oxacillin resistant (150) b
RP 59500 Vancomycin Ciprofloxacin Spiramycin Erythromycin Oxacillin
0.25-4 0.25-4 0.12->65 4->65 0.12-> 64 4->64
Coagulase-negative staphylococci Oxacillin RP 59500 susceptible (621) a Vancomycin Ciprofloxacin Spiramycin Erythromycin Oxacillin
0.03-4 0.03-8 0.03->64 0.03->64 0.03-> 64 0.03-2
0.5 1 0.25 4 0.5 0.25
1 2 1 >64 >64 2
0.12-8 0.12-4 0.03-> 64 0.25->64 0.03->64 4->64
0.5 2 0.25 >64 >64 32
1 2 8 >64 >64 >64
50%
90%
S. aureus
OxaciUin resistant (400) b
RP 59500 Vancomycin Ciprofloxacin Spiramycin Erythromycin Oxacillin
0.5 1 0.5 8 0.5 0.5 1 1 2 >64 >64 >64
1 1 1 16 >64 0.5 2 2 32 >64 >64 >64
aOxacillin MIC of ~<2 ~g/ml. bOxacillin MIC of/>4 ~g/ml.
TABLE 3
Effect of Resistance to E r y t h r o m y c i n or Ciprofloxacin o n Susceptibility of S t a p h y l o c o c c i to RP 59500 MIC (p~g/ml) Resistance Pattern
Range
50%
90%
S. au~'eus
Erythro-R a Erythro-S b Cipro-R c Cipro-S a
0.12-4 0.12-2 0.25-4 0.12-8
1 0.5 1 0.5
2 1 2 1
CNS e
Erythro-R a Erythro-S b Cipro-R C Cipro-S a
0.12-8 0.03--4 0.12-4 0.03-8
0.5 0.5 0.5 0.5
1 1 1 1
Organism
~Erythromycin resistant (MIC > 4 ~g/ml). bErythromycin susceptible (MIC < 1 ~g/ml). ~Ciprofloxacin resistant (MIC > 2 t~g/ml). dCiprofloxacin resistant (MIC < 2 ~g/ml). eCoagulase-negative staphylococci.
G.L. Archer et al.
226
TABLE 4
Susceptibility of Various Species of Coagulase-Negative Staphylococci to RP 59500 MIC (p~g/ml)
Organism (No. Tested) S. S. S. S. S. S. S. S. S.
capitis (10) cohnii (2) epidermidis (295) hemolyticus (35) hominis (50) saprophyticus (29) sciuri (2) simulans (14) warneri (21)
Range
50%
90%
0.25-1 1-4 0.12-4 0.25-8 0.12-1 0.25-2 1-2 0.25-1 0.25-2
0.5 -0.5 1 0.5 1 -0.5 0.5
1 -0.5 2 0.5 2 -1 1
centrations (MICs) (numerical values) of RP 59500 and each of the other agents tested. None of these correlation coefficients was significant. Finally, RP 59500 s h o w e d excellent activity against a subset of coagulase-negative staphylococci which were identified to the species level (Table 4). Overall, only 11 of 2066 staphylococci in this entire study required >2 ~g/ml RP 59500 for inhibition of growth.
RP 59500 has been s h o w n to be highly active against S. aureus and coagulase-negative staphylococci isolated from a variety of geographically diverse locations in North America. Indeed, there were no strains in this s t u d y for which the MIC of RP 59500 was >8 ~g/ml. Moreover, all but 11 of the 2066 unique isolates tested in this s t u d y were inhibited by ~ 2 ~g/ml of RP 59500. At the present time, susceptibility break points for RP 59500 have not been determined, but peak serum levels as high as 24 ~g/ml have been obtained with doses of RP 59500 that were well tolerated in h u m a n subjects (Etienne et al., 1992). The activity of RP 59500 against both oxacillinresistant and oxacillin-susceptible staphylococci and against organisms resistant to erythromycin, spiramycin, and ciprofloxacin suggests that it has special potential for the treatment of infections due to resistant staphylococci, and it m a y provide a viable alternative to vancomycin in this setting. This study was supported by a grant-in-aid from Rhone-Poulenc Rorer, Vitry-sur-Seine, France. The advice of Dr. D.H. Bouanchaud in the design and execution of this study is gratefully acknowledged.
REFERENCES
Aldridge KE, Schiro DD, Varner LM (1992) In vitro antistaphylococcal activity and testing of RP 59500, a new streptogramin, by two methods. Antimicrob Agents Chemother 36:854-855. Barriere JC, Bouanchaud DH, Paris JM, Rolin O, Harris NV, Smith C (1992) Antimicrobial activity against Staphylococcus aureus of semisynthetic injectable streptogramins: RP 59500 and related compounds. J Antimicrob Chemother 30(Suppl A):1-8. Bouanchaud DH (1992) In-vitro and in-vivo synergic activity and fractional inhibitory concentration (FIC) of the components of a semisynthetic streptogramin, RP 59500. J Antimicrob Chemother 30(Suppl A):95-99. Etienne SD, Montay G, LeLiboux A, Frydman A, Garaud JJ (1992) A phase I, double-blind, placebo-controlled study of the tolerance and pharmacokinetic behaviour
of RP 59500. J Antimicrob Chemother 30(Suppl A):123131. Fass RJ (1991) In vitro activity of RP 59500, a semisynthetic injectable pristinamycin, against staphylococci, streptococci and enterococci. Antimicrob Agents Chemother 35:553-559. Maple PAC, Hamilton-Miller JMT, Brumfitt W (1989) Worldwide antibiotic resistance in methicillin-resistant Staphylococcus aureus. Lancet 1:537-539. Maskell JP, Williams JD (1987) In vitro susceptibility of oral streptococci to pristinamycin. J Antimicrob Chemother 19:585-590. National Committee for Clinical Laboratory Standards (NCCLS) (1990) Approved standard, M7-A2: methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, 2nd ed. Villanova, PA: NCCLS.