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In vitro activity of mersacidin (M87-1551), an investigational peptide antibiotic tested against Gram-positive bloodstream isolates
DIAGN MICROBIOLINFECTDIS 1992;15:641-644
641
NOTE
In vitro Activity of Mersacidin (M87-1551), an Investigational Peptide Antibiotic Tested Against Gram-Positive Bloodstream Isolates Mary S. Barrett, Richard P. Wenzel, and Ronald N. Jones
We measured the in vitro activity of mersacidin (formerly M87-1551) against 183 clinical isolates (vancomycin susceptible) and 12 additional vancomycin-resistant strains of Grampositive bacteria. The activity for mersacidin increased an average twofold (range, 1.7- to 7.6-fold) in a calcium-enriched medium. The minimum inhibitory concentration (MIC)9o for mersacidin was 8-32 times higher than vancomycin for staphylococci, 4-64 times higher for enterococci, and up to 32 times higher for other organisms tested. The MICgo for MDL 62873,
a comparison compound, was <-0.5 i~g/ml for all species except Staphylococcus haemolyticus (MICgo, 4 I~g/ml), and it was >-4-fold more active than vancomycin. Against selected vancomycin-resistant strains, mersacidin had MICs ~16 i~g/ml for enterococci, 4-32 p~g/ml for Pediococcus, and ~2 i~g/ml for Leuconostoc species. Mersacidin may have some clinical utility in documented infections caused by staphylococci, nonenteric streptococci, Pediococcus, and Leuconostoc.
The isolation of Gram-positive pathogens has become an increasing clinical problem, especially among granulocytopenic patients (Viscoli et al., 1988). Moreover, certain traditional antimicrobial treatment modalities have been associated with the emergence of several other antimicrobial resistance patterns. Examples of the latter included ciprofloxacinresistant, coagulase-negative staphylococci (CNS) (Kotilainen et al., 1990), f~-lactamase-producing enterococci (Moellering, 1988), penicillin-binding protein-mediated ampicillin-resistant enterococci
(Sapico et al., 1989), quinolone resistance among methicillin-resistant Staphylococcus aureus (MRSA), and teicoplanin resistance among CNS. The glycopeptide vancomycin is commonly prescribed in the treatment of infections caused by these Gram-positive bacteria. Unlike most other antimicrobial agents, reports of vancomycin-resistant strains have been slow to emerge. Schwalbe et al. (1987) documented vancomycin-resistant Staphylococcus haemolyticus strains that were recovered following prophylaxis and therapy with vancomycin. This emergence of Gram-positive strains resistant to glycopeptides by varied mechanisms and the naturally resistant strains of Leuconostoc, Pediococcus, and Lactobacillus spp. (Nicas et al., 1989) have increased the resistance gene pool. Thus, alternative therapeutic agents appear to be warranted. The purpose of this study was to compare the in vitro activity of mersacidin (formerly M87-1551), a peptide compound that has modest Gram-positive in vitro activity (Ganguli et al., 1989; Niu and Neu, 1991) but disproportionately high in vivo potency
From the Department of Pathology(M.S.B., R.N.J.) and the Division of General Medicine (R.P.W.), Clinical Epidemiology and Health Services Research, Department of Internal Medicine, Universityof Iowa Collegeof Medicine, Iowa City, Iowa, USA. Address reprint requests to Prof. R.N. Jones, Department of Pathology, 5232 RCP, Universityof Iowa Hospitals and Clinics, Iowa City, IA 52242, USA. Received 1 December 1991; revised and accepted 10 January 1992. © 1992Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893/92/$5.00
642
M.S. Barrett et al.
(Ganguli et al., 1989; Hoechst India, data on file) with other related drugs. One of the comparison drugs was MDL 62873, an amide modification of the teicoplanin complex (Jones et al., 1991).
Antimicrobial Agents The antimicrobial agents tested were obtained as follows: mersacidin from Hoechst India (Bombay, India); MDL 62873 from Merrell Dow Research Institute, Lepetit Research Center (Gerenzano, Italy); and the other comparison compounds (vancomycin, ampicillin, ciprofloxacin, minocycline, and rifampin) from their US manufacturers.
Bacterial Strains The bacterial strains tested were principally bloodstream isolates from recent patient cultures at the University of Iowa Hospitals and Clinics (Iowa City, IA). Table 2 has a complete listing of the distribution of the 183 tested strains. A collection of 12 vancomycin-resistant strains, including five ampicillin-resistant Enterococcus spp., was obtained in part from the following sources: Hana Canawati, University of Southern California School of Medicine (Los Angeles, CA); David Preston, Lilly Research Laboratories (Indianapolis, IN); Dr. Daniel Sahm, University of Chicago (Chicago, IL); Jana Swenson, Centers for Disease Control (Atlanta, GA); and Dr. John Washington, The Cleveland Clinic Foundation (Cleveland, OH). For a listing of these six species, see Table 2.
Susceptibility Testing All susceptibility testing was performed according to the procedures recommended by the National Committee for Clinical Laboratory Standards (NCCLS, TABLE 1
1990). Appropriate quality control strains were processed to validate testing techniques and conditions. The effect of calcium concentration on the activity of mersacidin is illustrated in Table 1. Minimum inhibitory concentrations (MICs) determined in unsupplemented Muelter-Hinton broth with a minimum calcium level (<5 mg/L) were compared to those determined in divalent cation-supplemented Mueller-Hinton broth (see Table I note). An average twofold increase (range 1.7- to 7.6-fold) in mersacidin activity was observed in the enriched calcium environment. Divalent cation (calcium)-enhanced mersacidin activity may contribute to the in vivo success reported by Ganguli et al. (1989). The current standardized NCCLS broth dilution method requires a calcium concentration between those levels tested in this experiment (Table 1). All subsequently described mersacidin MICs were determined in cation-adjusted broth (NCCLS, 1990). The in vitro activities of mersacidin, vancomycin, and MDL 62873 when tested against 183 Grampositive, bacteremic isolates is summarized in Table 2. Mersacidin by the MICw750or MIC90 comparisons, was 4- to 64-fold less potent than vancomycin. Niu and Neu (1991) also observed that mersacidin was less active than vancomycin (four- to eightfold less) for the Staphylococcus spp. Highest mersacidin MICs (---32 ixg/ml) were found among S. haemolyticus, E. faecalis, E. faecium, Enterococcus spp., B-hemolytic Streptococcus spp., groups C, F, and G, and Bacillus cereus strains. Niu and Neu (1991) affirmed that nongroup-A B-hemolytic streptococci (groups B, C, and G) had elevated mersacidin MICs (8 ~xg/ml) compared with the Streptococcus pyogenes strains. MDL 62873 was generally ->4-fold more active than vancomycin. This finding was comparable to our earlier results (Jones et al., 1991) of two- to fourfold greater MDI 62873 activity against S. aureus, and 8- to 16fold greater MDL 62873 activity against CNS strains when compared with vancomycin. The highest MDL
Effects of the Broth Calcium Concentration on the Activity of Mersacidin Geometric Mean MIC (Dxg/ml)
Organism
No. Tested
Unsupplemented
Cation Supplemented ~
Staphylococcus aureus Oxacillin susceptible Oxacillin resistant S. epidermidis Streptococcus pneumoniae Group A Group B Listeria monocytogenes
20 10 10 10 10 10 10
18.8 18.4 27.2 3.7 2.0 8.0 57.6
8.5 8.2 13.6 2.2 0.6 4.0 7.6
aSupplemented to 50 mg/L calcium and 25 mg/L magnesium.
In vitro Activity of Mersacidin
TABLE 2
643
In vitro Mersacidin (M87-1551) Activity C o m p a r e d w i t h That of V a n c o m y c i n a n d MDL62873 Tested A g a i n s t 183 G r a m - P o s i t i v e Isolates
Mersacidin MIC (~g/ml)
Vancomycin MIC (~,g/ml)
MDL62873 MIC (~,g/ml)
No.
Organism Staphylococcus aureus Oxacillin susceptible Oxacillin resistant Staphylococcus epidermidis Staphylococcus haemolyticus Coagulase-negative staphylococci Enterococcus faecalis Enterococcus faecium Enterococcus spp. Streptococcus spp. Group A Group B Group C, F, G pneumoniae Corynebacterium jeikeium Bacillus cereus Listeria monocytogenes
Tested
50%
90%
Range
50%
90%
Range
20 10 20 I(Y 20b 17 10 I(Y
8 8 8 8 8 64 32 16
16 16 16 16 32 >64 64 32
1-32 1-32 1-32 ~0.5-64 1-32 32->64 32->64 8-32
~<0.5 ~0.5 1 2 1 1 ~<0.5 ~<0.5
~0.5 1 1 2 1 2 1 8
~0.5-1 0.06 ~0.5-1 0.12 ~<0.5-2 0.06 ~<0.5-4 1 ~0.5-1 0.06 ~<0.5-2 ~<0.5 ~<0.5-2 ~0.5 ~0.5-8 ~0.5
10 10 10 10d 10 6 10
~<2 4 4 <~2 8 32 8
~<2 4 16 4 8 -8
~2 ~2-8 ~2-64 ~2-4 ~>2--8 16-32 4-16
~0.5 ~<0.5 ~0.5 ~<0.5 ~0.5 ~<0.5 ~0.5 ~<0.5 ~<0.5 ~0.5 ~<0.5 ~<0.5 ~<0,5 ~<0.5 ~0.5 ~0.5 -~<0.5 1 1 ~0.5-2
50%
~0.5 ~<0.5 ~<0.5 ~0.5 ~<0.5 ~<0.5 ~<0.5
90%
Range
0.12 0.12 0.12 4 0.12 ~<0.5 ~<0.5 ~0.5
0.015-0.2 0.06-0.25 0.008-0.1 0.03-4 0.015-0.5 ~0.5 ~0.5 ~<0.5
~<0.5 ~0.5 ~<0.5 ~<0.5 ~0.5 -~<0.5
~<0.5 ~0.5 ~0.5 ~<0.5 ~0.5 ~0.5 ~0.5
aSeven strains were oxacillin resistant (~>4~,g/ml). blndudes S. hominis (4 strains), S. saprophyticus (4 strains), S. simulans (5 strains), S. warnerii (6 strains), and S. xylosus (1 strain). Three strains were oxacillin resistant. qncludes seven species, three isolates resistant to ampicillin (NCCLS, 1990). qncludes five strains resistant to penicillin (MIC ~>0.12 ~g/ml). 62873 MICs w e r e n o t e d a m o n g the S. haemolyticus strains, a fact that h a s b e e n p r e v i o u s l y r e p o r t e d for teicoplanin a n d its derivatives (Jones et al., 1991). A l t h o u g h v a n c o m y c i n - r e s i s t a n t Enterococcus spp. h a v e b e e n isolated at low rates, the increasing n u m ber of infections associated w i t h this p a t h o g e n (Moellering, 1988) causes s o m e concern. Similarly, Pediococcus spp. a n d Leuconostoc s p p . , are rarely isolated, but these o r g a n i s m s h a v e b e e n refractory to v a n c o m y c i n t h e r a p y especially a m o n g c o m p r o m i s e d patient g r o u p s (Nicas et al., 1989). W h e n w e tested six v a n c o m y c i n - r e s i s t a n t species, the six Enterococcus spp. d e m o n s t r a t e d c o m p l e t e m e r s a c i d i n cross-resistance with v a n c o m y c i n . O n e of three l o w - g r a d e v a n comydn-resistant E. faecalis isolates reported b y S a h m et al. (1989) r e m a i n e d susceptible to teicoplanin a n d its derivatives. Mersacidin M I C s w e r e --<2 p,g/ml for the Leuconostoc spp. and three of four pediococci were
inhibited b y -<8 ~g mersacidin/ml. All Pediococcus spp. a n d Leuconostoc spp. tested w e r e susceptible to ampicillin (MICs, -<0.5 ~g/ml), minocycline (MICs, -<1 ~g/ml), a n d r i f a m p i n (MICs, -<1 ~g/ml). Ciprofloxacin d e m o n s t r a t e d p o o r activity against these emerging Gram-positive p a t h o g e n s (data not shown). In s u m m a r y , no vancomycin-resistant strains were f o u n d a m o n g the 183 G r a m - p o s i t i v e clinical p a t h o gens. Elevated m e r s a c i d i n M I C s ( ~ 6 4 ~g/ml) for S, haemolyticus, E. faecalis, E. faecium, a n d Streptococcus spp. g r o u p s C. F, a n d G w e r e d o c u m e n t e d . Mersacidin s h o w e d best in vitro activity against staphylococci, n o n e n t e r i c Streptococcus s p p . , Pediococcus spp., a n d Leuconostoc spp. Thus, m e r s a c i d i n m a y be best suited for u s e in vivo against d o c u m e n t e d infections c a u s e d b y these species or u s e d as a lead structure for chemical modifications resulting in a more expanded Gram-positive spectrum.
REFERENCES Ganguli BN, Chatterjee S, Chatterjee S, Kogler H, Fehlhaber HW, Klesel N, Blumbach J (1989) Mersacidin, a novel peptide antibiotic: discovery and microbial evaluation [abst 413]. In Program and Abstracts of the Interscience Conference on Antimicrobial Agents and Chemother-
apy, Houston, TX. Washington, DC: American Society for Microbiology. Jones RN, Goldstein FW, Zhou XY (1991) Activities of two new teicoplanin amide derivatives (MDL 62211 and MDL 62873) compared with activities of teicoplanin and van-
644
comycin against 800 recent staphylococcal isolates from France and the United States. Antimicrob Agents Chem~ other 35:584-586. Kotilainen P, Nikoskelainen J, Huovinen P (1990) Emer~ gence of ciprofloxacin-resistant coagulase-negative staphylococcal skin flora in immunocompromised patients receiving ciprofloxacin. J Infect Dis 161:41-44. Moellering RC (1988) The enterococcus: high level resis~ tance to gentamicin and production of beta-lactamase. Clin Microbiol News 10:129-134. National Committee for Clinical Laboratory Standards (NCCLS) (1990) Approved standard, M7-A2: standard methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, 2nd ed. Villanova, PA: NCCLS. Nicas TI, Cole CT, Preston DA, Schabel AA, Nagarajan R (1989) Activity of glycopeptides against vancomycinresistance Gram-positive bacteria. Antimicrob Agents Chemother 33:1477-1481.
M.S. Barrett et al.
Niu WW, Neu HC (1991) Activity of mersacidin, a novel peptide, compared to that of vancomycin, teicoplanin and daptomycin. Antimicrob Agents Chemother 35:9981000. Sahm DF, Kissinger J, Gilmore MS, Murray PR, Mulder R, Solliday J, Clarke B (1989) In vitro susceptibility studies of vancomycin-resistant Enterococcus faecalis. Antimicrob Agents Chemother 33:1588-1591. Sapico FL, Canawati HN, Ginunas JV, Gilmore DS, Montgomerie JZ, Tuddenham WJ, Facklam RR (1989) Enterococci highly resistant to penicillin and ampicillin: an emerging clinical problem? J Clin Microbiol 27:20912095. Schwalbe RS, Stapelton JT, Gilligan PH (1987) Emergence of vancomycin-resistance in coagulase-negative staphylococci. N Engl J Med 316:927-931. Viscoli C, Van der Auwera P, Meunier F (1988) Grampositive infections in granulocytopenic patients: an important issue? J Antimicrob Chemother 21(Suppl C):149156.
641
NOTE
In vitro Activity of Mersacidin (M87-1551), an Investigational Peptide Antibiotic Tested Against Gram-Positive Bloodstream Isolates Mary S. Barrett, Richard P. Wenzel, and Ronald N. Jones
We measured the in vitro activity of mersacidin (formerly M87-1551) against 183 clinical isolates (vancomycin susceptible) and 12 additional vancomycin-resistant strains of Grampositive bacteria. The activity for mersacidin increased an average twofold (range, 1.7- to 7.6-fold) in a calcium-enriched medium. The minimum inhibitory concentration (MIC)9o for mersacidin was 8-32 times higher than vancomycin for staphylococci, 4-64 times higher for enterococci, and up to 32 times higher for other organisms tested. The MICgo for MDL 62873,
a comparison compound, was <-0.5 i~g/ml for all species except Staphylococcus haemolyticus (MICgo, 4 I~g/ml), and it was >-4-fold more active than vancomycin. Against selected vancomycin-resistant strains, mersacidin had MICs ~16 i~g/ml for enterococci, 4-32 p~g/ml for Pediococcus, and ~2 i~g/ml for Leuconostoc species. Mersacidin may have some clinical utility in documented infections caused by staphylococci, nonenteric streptococci, Pediococcus, and Leuconostoc.
The isolation of Gram-positive pathogens has become an increasing clinical problem, especially among granulocytopenic patients (Viscoli et al., 1988). Moreover, certain traditional antimicrobial treatment modalities have been associated with the emergence of several other antimicrobial resistance patterns. Examples of the latter included ciprofloxacinresistant, coagulase-negative staphylococci (CNS) (Kotilainen et al., 1990), f~-lactamase-producing enterococci (Moellering, 1988), penicillin-binding protein-mediated ampicillin-resistant enterococci
(Sapico et al., 1989), quinolone resistance among methicillin-resistant Staphylococcus aureus (MRSA), and teicoplanin resistance among CNS. The glycopeptide vancomycin is commonly prescribed in the treatment of infections caused by these Gram-positive bacteria. Unlike most other antimicrobial agents, reports of vancomycin-resistant strains have been slow to emerge. Schwalbe et al. (1987) documented vancomycin-resistant Staphylococcus haemolyticus strains that were recovered following prophylaxis and therapy with vancomycin. This emergence of Gram-positive strains resistant to glycopeptides by varied mechanisms and the naturally resistant strains of Leuconostoc, Pediococcus, and Lactobacillus spp. (Nicas et al., 1989) have increased the resistance gene pool. Thus, alternative therapeutic agents appear to be warranted. The purpose of this study was to compare the in vitro activity of mersacidin (formerly M87-1551), a peptide compound that has modest Gram-positive in vitro activity (Ganguli et al., 1989; Niu and Neu, 1991) but disproportionately high in vivo potency
From the Department of Pathology(M.S.B., R.N.J.) and the Division of General Medicine (R.P.W.), Clinical Epidemiology and Health Services Research, Department of Internal Medicine, Universityof Iowa Collegeof Medicine, Iowa City, Iowa, USA. Address reprint requests to Prof. R.N. Jones, Department of Pathology, 5232 RCP, Universityof Iowa Hospitals and Clinics, Iowa City, IA 52242, USA. Received 1 December 1991; revised and accepted 10 January 1992. © 1992Elsevier Science Publishing Co., Inc. 655 Avenue of the Americas, New York, NY 10010 0732-8893/92/$5.00
642
M.S. Barrett et al.
(Ganguli et al., 1989; Hoechst India, data on file) with other related drugs. One of the comparison drugs was MDL 62873, an amide modification of the teicoplanin complex (Jones et al., 1991).
Antimicrobial Agents The antimicrobial agents tested were obtained as follows: mersacidin from Hoechst India (Bombay, India); MDL 62873 from Merrell Dow Research Institute, Lepetit Research Center (Gerenzano, Italy); and the other comparison compounds (vancomycin, ampicillin, ciprofloxacin, minocycline, and rifampin) from their US manufacturers.
Bacterial Strains The bacterial strains tested were principally bloodstream isolates from recent patient cultures at the University of Iowa Hospitals and Clinics (Iowa City, IA). Table 2 has a complete listing of the distribution of the 183 tested strains. A collection of 12 vancomycin-resistant strains, including five ampicillin-resistant Enterococcus spp., was obtained in part from the following sources: Hana Canawati, University of Southern California School of Medicine (Los Angeles, CA); David Preston, Lilly Research Laboratories (Indianapolis, IN); Dr. Daniel Sahm, University of Chicago (Chicago, IL); Jana Swenson, Centers for Disease Control (Atlanta, GA); and Dr. John Washington, The Cleveland Clinic Foundation (Cleveland, OH). For a listing of these six species, see Table 2.
Susceptibility Testing All susceptibility testing was performed according to the procedures recommended by the National Committee for Clinical Laboratory Standards (NCCLS, TABLE 1
1990). Appropriate quality control strains were processed to validate testing techniques and conditions. The effect of calcium concentration on the activity of mersacidin is illustrated in Table 1. Minimum inhibitory concentrations (MICs) determined in unsupplemented Muelter-Hinton broth with a minimum calcium level (<5 mg/L) were compared to those determined in divalent cation-supplemented Mueller-Hinton broth (see Table I note). An average twofold increase (range 1.7- to 7.6-fold) in mersacidin activity was observed in the enriched calcium environment. Divalent cation (calcium)-enhanced mersacidin activity may contribute to the in vivo success reported by Ganguli et al. (1989). The current standardized NCCLS broth dilution method requires a calcium concentration between those levels tested in this experiment (Table 1). All subsequently described mersacidin MICs were determined in cation-adjusted broth (NCCLS, 1990). The in vitro activities of mersacidin, vancomycin, and MDL 62873 when tested against 183 Grampositive, bacteremic isolates is summarized in Table 2. Mersacidin by the MICw750or MIC90 comparisons, was 4- to 64-fold less potent than vancomycin. Niu and Neu (1991) also observed that mersacidin was less active than vancomycin (four- to eightfold less) for the Staphylococcus spp. Highest mersacidin MICs (---32 ixg/ml) were found among S. haemolyticus, E. faecalis, E. faecium, Enterococcus spp., B-hemolytic Streptococcus spp., groups C, F, and G, and Bacillus cereus strains. Niu and Neu (1991) affirmed that nongroup-A B-hemolytic streptococci (groups B, C, and G) had elevated mersacidin MICs (8 ~xg/ml) compared with the Streptococcus pyogenes strains. MDL 62873 was generally ->4-fold more active than vancomycin. This finding was comparable to our earlier results (Jones et al., 1991) of two- to fourfold greater MDI 62873 activity against S. aureus, and 8- to 16fold greater MDL 62873 activity against CNS strains when compared with vancomycin. The highest MDL
Effects of the Broth Calcium Concentration on the Activity of Mersacidin Geometric Mean MIC (Dxg/ml)
Organism
No. Tested
Unsupplemented
Cation Supplemented ~
Staphylococcus aureus Oxacillin susceptible Oxacillin resistant S. epidermidis Streptococcus pneumoniae Group A Group B Listeria monocytogenes
20 10 10 10 10 10 10
18.8 18.4 27.2 3.7 2.0 8.0 57.6
8.5 8.2 13.6 2.2 0.6 4.0 7.6
aSupplemented to 50 mg/L calcium and 25 mg/L magnesium.
In vitro Activity of Mersacidin
TABLE 2
643
In vitro Mersacidin (M87-1551) Activity C o m p a r e d w i t h That of V a n c o m y c i n a n d MDL62873 Tested A g a i n s t 183 G r a m - P o s i t i v e Isolates
Mersacidin MIC (~g/ml)
Vancomycin MIC (~,g/ml)
MDL62873 MIC (~,g/ml)
No.
Organism Staphylococcus aureus Oxacillin susceptible Oxacillin resistant Staphylococcus epidermidis Staphylococcus haemolyticus Coagulase-negative staphylococci Enterococcus faecalis Enterococcus faecium Enterococcus spp. Streptococcus spp. Group A Group B Group C, F, G pneumoniae Corynebacterium jeikeium Bacillus cereus Listeria monocytogenes
Tested
50%
90%
Range
50%
90%
Range
20 10 20 I(Y 20b 17 10 I(Y
8 8 8 8 8 64 32 16
16 16 16 16 32 >64 64 32
1-32 1-32 1-32 ~0.5-64 1-32 32->64 32->64 8-32
~<0.5 ~0.5 1 2 1 1 ~<0.5 ~<0.5
~0.5 1 1 2 1 2 1 8
~0.5-1 0.06 ~0.5-1 0.12 ~<0.5-2 0.06 ~<0.5-4 1 ~0.5-1 0.06 ~<0.5-2 ~<0.5 ~<0.5-2 ~0.5 ~0.5-8 ~0.5
10 10 10 10d 10 6 10
~<2 4 4 <~2 8 32 8
~<2 4 16 4 8 -8
~2 ~2-8 ~2-64 ~2-4 ~>2--8 16-32 4-16
~0.5 ~<0.5 ~0.5 ~<0.5 ~0.5 ~<0.5 ~0.5 ~<0.5 ~<0.5 ~0.5 ~<0.5 ~<0.5 ~<0,5 ~<0.5 ~0.5 ~0.5 -~<0.5 1 1 ~0.5-2
50%
~0.5 ~<0.5 ~<0.5 ~0.5 ~<0.5 ~<0.5 ~<0.5
90%
Range
0.12 0.12 0.12 4 0.12 ~<0.5 ~<0.5 ~0.5
0.015-0.2 0.06-0.25 0.008-0.1 0.03-4 0.015-0.5 ~0.5 ~0.5 ~<0.5
~<0.5 ~0.5 ~<0.5 ~<0.5 ~0.5 -~<0.5
~<0.5 ~0.5 ~0.5 ~<0.5 ~0.5 ~0.5 ~0.5
aSeven strains were oxacillin resistant (~>4~,g/ml). blndudes S. hominis (4 strains), S. saprophyticus (4 strains), S. simulans (5 strains), S. warnerii (6 strains), and S. xylosus (1 strain). Three strains were oxacillin resistant. qncludes seven species, three isolates resistant to ampicillin (NCCLS, 1990). qncludes five strains resistant to penicillin (MIC ~>0.12 ~g/ml). 62873 MICs w e r e n o t e d a m o n g the S. haemolyticus strains, a fact that h a s b e e n p r e v i o u s l y r e p o r t e d for teicoplanin a n d its derivatives (Jones et al., 1991). A l t h o u g h v a n c o m y c i n - r e s i s t a n t Enterococcus spp. h a v e b e e n isolated at low rates, the increasing n u m ber of infections associated w i t h this p a t h o g e n (Moellering, 1988) causes s o m e concern. Similarly, Pediococcus spp. a n d Leuconostoc s p p . , are rarely isolated, but these o r g a n i s m s h a v e b e e n refractory to v a n c o m y c i n t h e r a p y especially a m o n g c o m p r o m i s e d patient g r o u p s (Nicas et al., 1989). W h e n w e tested six v a n c o m y c i n - r e s i s t a n t species, the six Enterococcus spp. d e m o n s t r a t e d c o m p l e t e m e r s a c i d i n cross-resistance with v a n c o m y c i n . O n e of three l o w - g r a d e v a n comydn-resistant E. faecalis isolates reported b y S a h m et al. (1989) r e m a i n e d susceptible to teicoplanin a n d its derivatives. Mersacidin M I C s w e r e --<2 p,g/ml for the Leuconostoc spp. and three of four pediococci were
inhibited b y -<8 ~g mersacidin/ml. All Pediococcus spp. a n d Leuconostoc spp. tested w e r e susceptible to ampicillin (MICs, -<0.5 ~g/ml), minocycline (MICs, -<1 ~g/ml), a n d r i f a m p i n (MICs, -<1 ~g/ml). Ciprofloxacin d e m o n s t r a t e d p o o r activity against these emerging Gram-positive p a t h o g e n s (data not shown). In s u m m a r y , no vancomycin-resistant strains were f o u n d a m o n g the 183 G r a m - p o s i t i v e clinical p a t h o gens. Elevated m e r s a c i d i n M I C s ( ~ 6 4 ~g/ml) for S, haemolyticus, E. faecalis, E. faecium, a n d Streptococcus spp. g r o u p s C. F, a n d G w e r e d o c u m e n t e d . Mersacidin s h o w e d best in vitro activity against staphylococci, n o n e n t e r i c Streptococcus s p p . , Pediococcus spp., a n d Leuconostoc spp. Thus, m e r s a c i d i n m a y be best suited for u s e in vivo against d o c u m e n t e d infections c a u s e d b y these species or u s e d as a lead structure for chemical modifications resulting in a more expanded Gram-positive spectrum.
REFERENCES Ganguli BN, Chatterjee S, Chatterjee S, Kogler H, Fehlhaber HW, Klesel N, Blumbach J (1989) Mersacidin, a novel peptide antibiotic: discovery and microbial evaluation [abst 413]. In Program and Abstracts of the Interscience Conference on Antimicrobial Agents and Chemother-
apy, Houston, TX. Washington, DC: American Society for Microbiology. Jones RN, Goldstein FW, Zhou XY (1991) Activities of two new teicoplanin amide derivatives (MDL 62211 and MDL 62873) compared with activities of teicoplanin and van-
644
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