- Email: [email protected]
Comparative antimicrobial activity of ABT-773, a novel ketolide, tested against drug-resistant Gram-positive cocci and Haemophilus influenzae
International Journal of Antimicrobial Agents 17 (2001) 451– 455 www.ischemo.org
Original article
Comparative antimicrobial activity of ABT-773, a novel ketolide, tested against drug-resistant Gram-positive cocci and Haemophilus influenzae Maria Fernanda Rospide 1, Douglas J. Biedenbach, Ronald N. Jones * Uni6ersity of Iowa College of Medicine, Iowa City, IA 52242, USA Received 12 January 2001; accepted 23 January 2001
Abstract The antimicrobial activity of ABT-773, a novel ketolide, was tested against 618 Gram-positive strains collected from various surveillance programmes between 1997 and 2000. ABT-773 has potent activity against Streptococcus pneumoniae (MIC90, 50.03–0.12 mg/l), b-haemolytic streptococci (MIC90, 50.03 mg/l) and viridans group streptococci (MIC90, 50.03 mg/l), including erythromycin-resistant strains. In contrast, ABT-773 was less active against erythromycin-resistant Staphylococcus aureus (31% susceptible at 5 0.25 mg/l), coagulase-negative staphylococci (41% susceptible) and enterococci (30% susceptible). Haemophilus influenzae (MIC90, 4 mg/l) was less inhibited by the two ketolides tested, and ABT-773 was generally two- to fourfold more potent than telithromycin. The ketolides appear to have potential clinical use against some Gram-positive species resistant to macrolides. © 2001 Published by Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. Keywords: Ketolides; ABT-773; Gram-positive
1. Introduction Infections caused by Gram-positive organisms are of major concern due to the increased incidence and the high level of multi-drug resistance [1,2]. Increased macrolide resistance has been detected at variable rates in different epidemiological settings among Streptococcus spp., Staphylococcus aureus and enterococci [3,4]. New orally administered drugs with broader ranges of activity and greater potency are needed. Ketolides are a new class of semi-synthetic (14-membered-ring) macrolide derivatives characterised by a * Corresponding author. The JONES Group, 345 Beaver Kreek Centre, Suite A, North Liberty, IA 52317, USA. Tel.: +1-3196653370; fax: + 1-319-6653371. E-mail address: [email protected] (R.N. Jones). 1 Current address: CEMIC, Bacteriology Laboratory, Billinghurst 2447, (1425) Capital Federal, Argentina.
keto group replacing the L-cladinose moiety at position 3 which appears to increase their stability in weakly acidic environments [5]. Additional alkyl-aryl extensions at positions 11 and 12 of its lactone ring are also present. Previously published reports indicate that ketolides are weak inducers of MLSB resistance [6,7]. In recent studies, a new ketolide ABT-773 (formerly A-195773) [8] showed potent antibacterial activity against S. pneumoniae, Moraxella catarrhalis, Chlamydia pneumoniae and Haemophilus influenzae, including multi-resistant strains [9–11]. Potency versus some anaerobes and Helicobacter pylori has also been reported [12,13]. The purpose of this study was to compare the in vitro activities of ABT-773, with those of telithromycin, another ketolide, clindamycin, quinupristin-dalfopristin, ampicillin, penicillin, oxacillin and vancomycin against erythromycin-susceptible and -resistant Gram-positive microorganisms and H. influenzae.
0924-8579/01/$20 © 2001 Published by Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. PII: S 0 9 2 4 - 8 5 7 9 ( 0 1 ) 0 0 3 3 2 - 6
452
M.F. Rospide et al. / International Journal of Antimicrobial Agents 17 (2001) 451–455
Table 1 Antimicrobial activity of ABT-773 compared with telithromycin and eight other compounds tested against 618 strains of Gram-positive pathogens and 97 strains of H. influenzae Organism (no. tested)
Antimicrobial agent
MIC (mg/l) 50%
Cumulative % inhibited at MIC (mg/l) 90%
50.25
0.5
1
2
Bacillus spp. (12)
ABT-773 Telithromycin Erythromycin Clindamycin Quinupristin/dalfopristin Ampicillin Penicillin Oxacillin Vancomycin
50.03 0.12 0.5 1 1 1 4 8 1
0.06 0.5 \8 \8 1 16 16 \8 1
91 82 42 0 0 25 33 8 18
100 100 50 8 46 42 42 17 36
100 100 75 58 91 50 42 33 100
100 100 75 67 100 67 42 33 100
Corynebacterium spp. (19)
ABT-773 Telithromycin Erythromycin Clindamycin Quinupristin/dalfopristin Ampicillin Penicillin Oxacillin Vancomycin
50.03 50.015 \8 \8 0.25 \16 8 \8 0.5
0.25 0.12 \8 \8 0.5 \16 \32 \8 0.5
95 100 5 5 53 16 32 0 32
100 100 5 5 95 26 32 5 90
100 100 5 5 100 32 32 5 100
100 100 5 5 100 32 42 11 100
ABT-773 Telithromycin Clindamycin Quinupristin/dalfopristin Ampicillin Penicillin Vancomycin
50.03 0.03 \8 4 1 2 1
50.03 0.03 \8 8 2 8 2
100 100 22 11 33 33 22
100 100 22 11 56 33 33
100 100 22 22 100 33 89
100 100 22 33 100 78 100
30 22 2 2 0 0 2
30 26 9 33 4 0 7
30 26 11 50 22 0 37
30 30 11 57 39 17 41
100 100 100 93 22 46 0
100 100 100 98 29 73 2
100 100 100 98 32 83 90
100 100 100 100 42 85 100
31 31 28 32 6 8 0
31 31 30 87 8 14 10
31 31 30 98 9 15 89
31 31 30 100 10 15 100
94 94 100 94 44 69 0
94 94 100 100 56 75 6
94 94 100 100 63 75 44
94 94 100 100 69 81 100
Enterococcia Erythromycin-susc. (10)
Erythromycin-resist. (46)
S. aureus Erythromycin-susc. (41)
Erythromycin-resist. (103)
CoNSb Erythromycin-susc. (16)
ABT-773 Telithromycin Clindamycin Quinupristin/dalfopristin Ampicillin Penicillin Vancomycin ABT-773 Telithromycin Clindamycin Quinupristin/dalfopristin Penicillin Oxacillin Vancomycin ABT-773 Telithromycin Clindamycin Quinupristin/dalfopristin Penicillin Oxacillin Vancomycin ABT-773 Telithromycin Clindamycin Quinupristin/dalfopristin Penicillin Oxacillin Vancomycin
16 8 \8 1 \16 \32 \16 50.03 0.12 0.12 0.25 4 0.5 1 \32 \32 \8 0.5 32 \8 1 50.03 0.12 50.06 0.25 0.5 0.12 2
32 32 \8 \8 \16 \32 \16 0.06 0.25 0.12 0.25 32 \8 1 \32 \32 \8 1 \32 \8 2 0.06 0.25 0.12 0.25 32 \8 2
M.F. Rospide et al. / International Journal of Antimicrobial Agents 17 (2001) 451–455
453
Table 1 (Continued) Organism (no. tested)
Erythromycin-resist. (51)
S. pneumoniae Erythromycin-susc. (59)
Antimicrobial agent
ABT-773 Telithromycin Clindamycin Quinupristin/dalfopristin Penicillin Oxacillin Vancomycin
MIC (mg/l)
Cumulative % inhibited at MIC (mg/l)
50%
90%
\32 \32 \8 0.25 8 \8 2
\32 \32 \8 1 \32 \8 2
50.25
0.5
1
2
41 37 35 67 6 10 0
41 41 35 82 8 12 4
41 41 39 90 12 14 29
41 41 39 90 22 26 94
ABT-773 Telithromycin Clindamycin Quinupristin/dalfopristin Penicillin Oxacillin Vancomycin
50.03 50.015 50.25 0.25 50.03 50.06 0.25
50.03 50.015 50.25 0.5 1 2 0.5
100 100 100 75 78 79 54
100 100 100 100 86 86 98
100 100 100 100 93 86 100
100 100 100 100 100 100 100
ABT-773 Telithromycin Clindamycin Quinupristin/dalfopristin Penicillin Oxacillin Vancomycin
50.03 0.12 50.25 0.5 2 8 0.5
0.12 0.5 \2 0.5 4 \8 0.5
95 75 67 49 24 0 44
98 95 67 95 33 0 100
100 100 67 98 44 0 100
100 100 67 100 86 0 100
ABT-773 Telithromycin Clindamycin Quinupristin/dalfopristin Penicillin Oxacillin Vancomycin
50.03 50.015 50.06 0.25 50.015 50.06 0.5
50.03 50.015 50.06 0.5 0.06 0.25 0.5
100 100 100 81 100 94 29
100 100 100 99 100 100 96
100 100 100 100 100 100 100
100 100 100 100 100 100 100
ABT-773 Telithromycin Clindamycin Quinupristin/dalfopristin Penicillin Oxacillin Vancomycin
50.03 0.03 \8 0.25 0.03 0.25 0.5
50.03 0.25 \8 0.5 0.06 0.5 0.5
100 94 38 75 100 81 25
100 94 44 100 100 100 94
100 94 44 100 100 100 100
100 94 44 100 100 100 100
ABT-773 Telithromycin Clindamycin Quinupristin/dalfopristin Penicillin Oxacillin Vancomycin
50.03 50.015 50.06 0.5 50.015 50.06 0.5
50.03 50.015 50.06 1 4 1 1
100 100 100 25 77 80 13
100 100 100 64 86 88 78
100 100 100 98 86 94 98
100 100 100 100 86 96 100
Erythromycin-resist. (51)
ABT-773 Telithromycin Clindamycin Quinupristin/dalfopristin Penicillin Oxacillin Vancomycin
50.03 0.06 50.06 0.5 0.25 0.5 0.5
50.03 0.25 \8 1 8 8 1
98 96 82 20 53 46 6
98 98 82 75 63 72 88
100 98 82 100 63 82 100
100 98 82 100 63 87 100
H. influenzae (97)
ABT-773 Telithromycin Erythromycin Quinupristin/dalfopristin Ampicillin
2 4 4 \2 50.5
4 8 8 \2 \4
0 0 1 0 55
9 0 2 1 61
60 14 21 39 62
Erythromycin-resist. (55)
b-Haemolytic streptococci Erythromycin-susc. (83)
Erythromycin-resist. (16)
Viridans group streptococci Erythromycin-susc. (56)
a
Includes five species. CoNS, coagulase-negative staphylococci. c –, Untested concentration. b
0 0 0 0 –c
454
M.F. Rospide et al. / International Journal of Antimicrobial Agents 17 (2001) 451–455
2. Materials and methods
2.1. Strains A total of 618 Gram-positive organisms including erythromycin-susceptible and erythromycin-resistant enterococci (56), S. aureus (144), coagulase-negative staphylococci (CoNS, 67), S. pneumoniae (114), bhaemolytic streptococci (99), viridans group streptococci (107), Bacillus spp. (12), Corynebacterium spp. (19) and 97 strains of H. influenzae were tested. These microorganisms were collected from clinical specimens of various body sites provided by participants in several international surveillance programmes.
2.2. Antimicrobials and susceptibility methods ABT-773 was provided by Abbott Laboratories (North Chicago, IL, USA). All other antimicrobials were provided by their respective manufacturers or from commercial vendors (Sigma, St. Louis, MO, USA). MICs were determined by broth microdilution susceptibility testing according to the recommendations of the National Committee for Clinical Laboratory Standards (NCCLS) M7-A5 document [14]. Quality control ranges for MIC testing have been determined earlier by our laboratories [15].
ABT-773 exhibited good in vitro activity against all strains of S. pneumoniae tested regardless of their resistance to erythromycin or penicillin. ABT-773 had the lowest MICs of the two ketolides tested (MIC90, 50.03 mg/l) against erythromycin-resistant strains, but both achieved total inhibition at the same concentration (MIC, 1 mg/l). Similar potency was observed against b-haemolytic streptococci when the MICs of ketolides were compared with those of erythromycin. Both ketolides retained acceptable activity against macrolideresistant b-haemolytic streptococci (MIC90, 50.03 mg/l). All antimicrobials tested against the streptococcus viridans group showed excellent activity and no cross-resistance was observed between ABT-773 and the macrolides. All Corynebacterium spp. (except one strain) were fully resistant to erythromycin and clindamycin using the breakpoint proposed by the NCCLS for non-fastidious microorganisms and staphylococci. None of the ketolides showed cross-resistance with erythromycin or clindamycin (MIC90, 0.25 mg/l) against Corynebacterium spp. or Bacillus spp. The potency of ABT-773 (MIC90, 4 mg/l) was twofold greater than that of telithromycin and erythromycin (MIC90, 8 mg/l) against H. influenzae. Over one-half of the H. influenzae strains had an ABT-773 MIC of 2 mg/l.
4. Conclusion 3. Results The antimicrobial activity of ABT-773 compared with telithromycin and eight other compounds tested against 618 strains of Gram-positive pathogens and 97 strains of H. influenzae is shown in Table 1. ABT-773 showed good activity against erythromycin-susceptible S. aureus (MIC90, 0.06 mg/l) and CoNS (MIC90, 0.06 mg/l). However, erythromycin-resistant staphylococci (MIC90, ]32 mg/l) were not inhibited by clinically relevant ketolide concentrations. The MIC90 of ABT773 (0.06 mg/l) was fourfold lower compared with that of telithromycin (MIC90, 0.25 mg/l) for erythromycinsusceptible staphylococci strains. The vast majority of the erythromycin-resistant strains were also resistant to penicillin, oxacillin, clindamycin and telithromycin, but were inhibited by quinupristin-dalfopristin (MIC90, 1 mg/l) and vancomycin (MIC90, 2 mg/l). ABT-773 showed comparable activity to telithromycin against erythromycin-susceptible enterococci, displaying the best performance of all antimicrobials tested (MIC90, 0.03 mg/l). None of the drugs showed good activity against vancomycin-resistant enterococci; however, quinupristin-dalfopristin was the most potent drug (MIC50, 1 mg/l) against Enterococcus faecium isolates.
The results of the current study indicate that ABT773 has potent in vitro activity against S. pneumoniae, b-haemolytic and viridans group streptococci, even against isolates harbouring the MLSB resistance phenotype. These results are consistent with other studies [8,10]. Similar observations were reported for other ketolides such as telithromycin (RU-66647, HMR 3647) and HMR 3004 (RU 64004) [16–18]. ABT-773 showed poor activity against erythromycin-resistant S. aureus, CoNS- and vancomycin- and erythromycin-resistant enterococci. Very similar activities were achieved by both ketolides against Gram-positive microorganisms and H. influenzae overall, but ABT-773 appeared to be significantly more potent against susceptible strains. ABT-773 may be useful for the treatment of some Gram-positive respiratory tract and skin and soft tissue infections resistant to macrolides, especially those caused by streptococci. Further studies are needed to assess the clinical efficacy of this drug class against erythromycin-resistant pathogen subsets and the Haemophilus spp.
Acknowledgements The co-authors express their gratitude for the input
M.F. Rospide et al. / International Journal of Antimicrobial Agents 17 (2001) 451–455
and support of K. Meyer, M. Beach, M. Erwin and M. Pfaller. This investigation was made possible by funds from the Department of Pathology, University of Iowa College of Medicine, Iowa City, Iowa. Dr Rospide was the recipient of the SENTRY Programme Fellowship for the year 2000 (Bristol-Myers Squibb).
[9]
[10]
References [1] Jones RN, Pfaller MA. Bacterial resistance: a worldwide problem. Diagn Microbiol Infect Dis 1998;31:379 –88. [2] Pfaller MA, Jones RN, Doern GV, Sader HS, Kugler KC, Beach ML. Survey of blood stream infections attributable to gram-positive cocci: frequency of occurrence and antimicrobial susceptibility of isolates collected in 1997 in the United States, Canada, and Latin America from the SENTRY Antimicrobial Surveillance Program. SENTRY Participants Group. Diagn Microbiol Infect Dis 1999;33:283 –97. [3] Jones RN, Pfaller MA. Macrolide and fluoroquinolone (levofloxacin) resistances among Streptococcus pneumoniae strains: significant trends from the SENTRY antimicrobial surveillance program (North America, 1997 – 1999). J Clin Microbiol 2000;38:4298 –9. [4] Schmitz FJ, Verhoef J, Fluit AC. Prevalence of resistance to MLS antibiotics in 20 European university hospitals participating in the European SENTRY surveillance programme. Sentry Participants Group. J Antimicrob Chemother 1999;43:783 – 92. [5] Carbon C, Young L. Ketolides and other derivatives. In: Zinner SH, Young LS, Acar JF, Neu HN, editors. Expanding indications for the new macrolides, azalides and streptogramins. New York, NY: Marcel Dekker Inc, 1997:121 – 3. [6] Bonnefoy A, Girard AM, Agouridas C, Chantot JF. Ketolides lack inducibility properties of MLS(B) resistance phenotype. J Antimicrob Chemother 1997;40:85 –90. [7] Zhong P, Cao Z, Hammond R, et al. Induction of ribosome methylation in MLS-resistant Streptococcus pneumoniae by macrolides and ketolides. Microb Drug Resist 1999;5:183 – 8. [8] Capobianco JO, Cao Z, Shortridge VD, Ma Z, Flamm RK, Zhong P. Studies of the novel ketolide ABT-773: transport, binding to ribosomes and inhibition of protein synthesis in
.
[11]
[12]
[13]
[14]
[15]
[16] [17]
[18]
455
Streptococcus pneumoniae. Antimicrob Agents Chemother 2000;44:1562 – 7. Brueggemann AB, Doern GV, Huynh HK, Wingert EM, Rhomberg PR. In vitro activity of ABT-773, a new ketolide, against recent clinical isolates of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Antimicrob Agents Chemother 2000;44:447 – 9. Davies TA, Ednie LM, Hoellman DM, Pankuch GA, Jacobs MR, Appelbaum PC. Antipneumococcal activity of ABT-773 compared to those of 10 other agents. Antimicrob Agents Chemother 2000;44:1894 – 9. Strigl S, Roblin PM, Reznik T, Hammerschlag MR. In vitro activity of ABT 773, a new ketolide antibiotic, against Chlamydia pneumoniae. Antimicrob Agents Chemother 2000;44:1112 –3. Goldstein EJC, Citron DM, Merriam CV, Warren Y, Tyrrell K. Comparative in vitro activities of ABT-773 against aerobic and anaerobic pathogens isolated from skin and soft-tissue animal and human bite wound infections. Antimicrob Agents Chemother 2000;44:2525 – 9. Pendland SL, Prause JL, Neuhauser MM, Boyea N, Hackleman JM, Danziger LH. Invitro activities of a new ketolide, ABT-773, alone and in combination with amoxicillin, metronidazole, or tetracycline against Helicobacter pylori. Antimicrob Agents Chemother 2000;44:2518 – 20. National Committee for Clinical Laboratory Standards. Methods for dilution antimicrobial susceptibility tests for bacteria that grows aerobically. Approved standard M7-A5, 5th ed. Wayne, PA: National Committee for Clinical Laboratory Standards, 2000. Marshall SA, Erwin ME, Jones RN. Determination of MIC quality control ranges for ABT-773, a novel ketolide antimicrobial agent. J Clin Microbiol 2000;38:2462 – 3. Jones RN, Biedenbach DJ. Antimicrobial activity of RU-66647, a new ketolide. Diagn Microbiol Infect Dis 1997;27:7 – 12. Jamjian C, Biedenbach DJ, Jones RN. In vitro evaluation of a novel ketolide antimicrobial agent, RU-64004. Antimicrob Agents Chemother 1997;41:454 – 9. Pankuch GA, Visalli MA, Jacobs MR, Appelbaum PC. Susceptibilities of penicillin- and erythromycin-susceptible and -resistant pneumococci to HMR 3647 (RU 66647), a new ketolide, compared with susceptibilities to 17 other agents. Antimicrob Agents Chemother 1998;42:624 – 30.
Original article
Comparative antimicrobial activity of ABT-773, a novel ketolide, tested against drug-resistant Gram-positive cocci and Haemophilus influenzae Maria Fernanda Rospide 1, Douglas J. Biedenbach, Ronald N. Jones * Uni6ersity of Iowa College of Medicine, Iowa City, IA 52242, USA Received 12 January 2001; accepted 23 January 2001
Abstract The antimicrobial activity of ABT-773, a novel ketolide, was tested against 618 Gram-positive strains collected from various surveillance programmes between 1997 and 2000. ABT-773 has potent activity against Streptococcus pneumoniae (MIC90, 50.03–0.12 mg/l), b-haemolytic streptococci (MIC90, 50.03 mg/l) and viridans group streptococci (MIC90, 50.03 mg/l), including erythromycin-resistant strains. In contrast, ABT-773 was less active against erythromycin-resistant Staphylococcus aureus (31% susceptible at 5 0.25 mg/l), coagulase-negative staphylococci (41% susceptible) and enterococci (30% susceptible). Haemophilus influenzae (MIC90, 4 mg/l) was less inhibited by the two ketolides tested, and ABT-773 was generally two- to fourfold more potent than telithromycin. The ketolides appear to have potential clinical use against some Gram-positive species resistant to macrolides. © 2001 Published by Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. Keywords: Ketolides; ABT-773; Gram-positive
1. Introduction Infections caused by Gram-positive organisms are of major concern due to the increased incidence and the high level of multi-drug resistance [1,2]. Increased macrolide resistance has been detected at variable rates in different epidemiological settings among Streptococcus spp., Staphylococcus aureus and enterococci [3,4]. New orally administered drugs with broader ranges of activity and greater potency are needed. Ketolides are a new class of semi-synthetic (14-membered-ring) macrolide derivatives characterised by a * Corresponding author. The JONES Group, 345 Beaver Kreek Centre, Suite A, North Liberty, IA 52317, USA. Tel.: +1-3196653370; fax: + 1-319-6653371. E-mail address: [email protected] (R.N. Jones). 1 Current address: CEMIC, Bacteriology Laboratory, Billinghurst 2447, (1425) Capital Federal, Argentina.
keto group replacing the L-cladinose moiety at position 3 which appears to increase their stability in weakly acidic environments [5]. Additional alkyl-aryl extensions at positions 11 and 12 of its lactone ring are also present. Previously published reports indicate that ketolides are weak inducers of MLSB resistance [6,7]. In recent studies, a new ketolide ABT-773 (formerly A-195773) [8] showed potent antibacterial activity against S. pneumoniae, Moraxella catarrhalis, Chlamydia pneumoniae and Haemophilus influenzae, including multi-resistant strains [9–11]. Potency versus some anaerobes and Helicobacter pylori has also been reported [12,13]. The purpose of this study was to compare the in vitro activities of ABT-773, with those of telithromycin, another ketolide, clindamycin, quinupristin-dalfopristin, ampicillin, penicillin, oxacillin and vancomycin against erythromycin-susceptible and -resistant Gram-positive microorganisms and H. influenzae.
0924-8579/01/$20 © 2001 Published by Elsevier Science B.V. and International Society of Chemotherapy. All rights reserved. PII: S 0 9 2 4 - 8 5 7 9 ( 0 1 ) 0 0 3 3 2 - 6
452
M.F. Rospide et al. / International Journal of Antimicrobial Agents 17 (2001) 451–455
Table 1 Antimicrobial activity of ABT-773 compared with telithromycin and eight other compounds tested against 618 strains of Gram-positive pathogens and 97 strains of H. influenzae Organism (no. tested)
Antimicrobial agent
MIC (mg/l) 50%
Cumulative % inhibited at MIC (mg/l) 90%
50.25
0.5
1
2
Bacillus spp. (12)
ABT-773 Telithromycin Erythromycin Clindamycin Quinupristin/dalfopristin Ampicillin Penicillin Oxacillin Vancomycin
50.03 0.12 0.5 1 1 1 4 8 1
0.06 0.5 \8 \8 1 16 16 \8 1
91 82 42 0 0 25 33 8 18
100 100 50 8 46 42 42 17 36
100 100 75 58 91 50 42 33 100
100 100 75 67 100 67 42 33 100
Corynebacterium spp. (19)
ABT-773 Telithromycin Erythromycin Clindamycin Quinupristin/dalfopristin Ampicillin Penicillin Oxacillin Vancomycin
50.03 50.015 \8 \8 0.25 \16 8 \8 0.5
0.25 0.12 \8 \8 0.5 \16 \32 \8 0.5
95 100 5 5 53 16 32 0 32
100 100 5 5 95 26 32 5 90
100 100 5 5 100 32 32 5 100
100 100 5 5 100 32 42 11 100
ABT-773 Telithromycin Clindamycin Quinupristin/dalfopristin Ampicillin Penicillin Vancomycin
50.03 0.03 \8 4 1 2 1
50.03 0.03 \8 8 2 8 2
100 100 22 11 33 33 22
100 100 22 11 56 33 33
100 100 22 22 100 33 89
100 100 22 33 100 78 100
30 22 2 2 0 0 2
30 26 9 33 4 0 7
30 26 11 50 22 0 37
30 30 11 57 39 17 41
100 100 100 93 22 46 0
100 100 100 98 29 73 2
100 100 100 98 32 83 90
100 100 100 100 42 85 100
31 31 28 32 6 8 0
31 31 30 87 8 14 10
31 31 30 98 9 15 89
31 31 30 100 10 15 100
94 94 100 94 44 69 0
94 94 100 100 56 75 6
94 94 100 100 63 75 44
94 94 100 100 69 81 100
Enterococcia Erythromycin-susc. (10)
Erythromycin-resist. (46)
S. aureus Erythromycin-susc. (41)
Erythromycin-resist. (103)
CoNSb Erythromycin-susc. (16)
ABT-773 Telithromycin Clindamycin Quinupristin/dalfopristin Ampicillin Penicillin Vancomycin ABT-773 Telithromycin Clindamycin Quinupristin/dalfopristin Penicillin Oxacillin Vancomycin ABT-773 Telithromycin Clindamycin Quinupristin/dalfopristin Penicillin Oxacillin Vancomycin ABT-773 Telithromycin Clindamycin Quinupristin/dalfopristin Penicillin Oxacillin Vancomycin
16 8 \8 1 \16 \32 \16 50.03 0.12 0.12 0.25 4 0.5 1 \32 \32 \8 0.5 32 \8 1 50.03 0.12 50.06 0.25 0.5 0.12 2
32 32 \8 \8 \16 \32 \16 0.06 0.25 0.12 0.25 32 \8 1 \32 \32 \8 1 \32 \8 2 0.06 0.25 0.12 0.25 32 \8 2
M.F. Rospide et al. / International Journal of Antimicrobial Agents 17 (2001) 451–455
453
Table 1 (Continued) Organism (no. tested)
Erythromycin-resist. (51)
S. pneumoniae Erythromycin-susc. (59)
Antimicrobial agent
ABT-773 Telithromycin Clindamycin Quinupristin/dalfopristin Penicillin Oxacillin Vancomycin
MIC (mg/l)
Cumulative % inhibited at MIC (mg/l)
50%
90%
\32 \32 \8 0.25 8 \8 2
\32 \32 \8 1 \32 \8 2
50.25
0.5
1
2
41 37 35 67 6 10 0
41 41 35 82 8 12 4
41 41 39 90 12 14 29
41 41 39 90 22 26 94
ABT-773 Telithromycin Clindamycin Quinupristin/dalfopristin Penicillin Oxacillin Vancomycin
50.03 50.015 50.25 0.25 50.03 50.06 0.25
50.03 50.015 50.25 0.5 1 2 0.5
100 100 100 75 78 79 54
100 100 100 100 86 86 98
100 100 100 100 93 86 100
100 100 100 100 100 100 100
ABT-773 Telithromycin Clindamycin Quinupristin/dalfopristin Penicillin Oxacillin Vancomycin
50.03 0.12 50.25 0.5 2 8 0.5
0.12 0.5 \2 0.5 4 \8 0.5
95 75 67 49 24 0 44
98 95 67 95 33 0 100
100 100 67 98 44 0 100
100 100 67 100 86 0 100
ABT-773 Telithromycin Clindamycin Quinupristin/dalfopristin Penicillin Oxacillin Vancomycin
50.03 50.015 50.06 0.25 50.015 50.06 0.5
50.03 50.015 50.06 0.5 0.06 0.25 0.5
100 100 100 81 100 94 29
100 100 100 99 100 100 96
100 100 100 100 100 100 100
100 100 100 100 100 100 100
ABT-773 Telithromycin Clindamycin Quinupristin/dalfopristin Penicillin Oxacillin Vancomycin
50.03 0.03 \8 0.25 0.03 0.25 0.5
50.03 0.25 \8 0.5 0.06 0.5 0.5
100 94 38 75 100 81 25
100 94 44 100 100 100 94
100 94 44 100 100 100 100
100 94 44 100 100 100 100
ABT-773 Telithromycin Clindamycin Quinupristin/dalfopristin Penicillin Oxacillin Vancomycin
50.03 50.015 50.06 0.5 50.015 50.06 0.5
50.03 50.015 50.06 1 4 1 1
100 100 100 25 77 80 13
100 100 100 64 86 88 78
100 100 100 98 86 94 98
100 100 100 100 86 96 100
Erythromycin-resist. (51)
ABT-773 Telithromycin Clindamycin Quinupristin/dalfopristin Penicillin Oxacillin Vancomycin
50.03 0.06 50.06 0.5 0.25 0.5 0.5
50.03 0.25 \8 1 8 8 1
98 96 82 20 53 46 6
98 98 82 75 63 72 88
100 98 82 100 63 82 100
100 98 82 100 63 87 100
H. influenzae (97)
ABT-773 Telithromycin Erythromycin Quinupristin/dalfopristin Ampicillin
2 4 4 \2 50.5
4 8 8 \2 \4
0 0 1 0 55
9 0 2 1 61
60 14 21 39 62
Erythromycin-resist. (55)
b-Haemolytic streptococci Erythromycin-susc. (83)
Erythromycin-resist. (16)
Viridans group streptococci Erythromycin-susc. (56)
a
Includes five species. CoNS, coagulase-negative staphylococci. c –, Untested concentration. b
0 0 0 0 –c
454
M.F. Rospide et al. / International Journal of Antimicrobial Agents 17 (2001) 451–455
2. Materials and methods
2.1. Strains A total of 618 Gram-positive organisms including erythromycin-susceptible and erythromycin-resistant enterococci (56), S. aureus (144), coagulase-negative staphylococci (CoNS, 67), S. pneumoniae (114), bhaemolytic streptococci (99), viridans group streptococci (107), Bacillus spp. (12), Corynebacterium spp. (19) and 97 strains of H. influenzae were tested. These microorganisms were collected from clinical specimens of various body sites provided by participants in several international surveillance programmes.
2.2. Antimicrobials and susceptibility methods ABT-773 was provided by Abbott Laboratories (North Chicago, IL, USA). All other antimicrobials were provided by their respective manufacturers or from commercial vendors (Sigma, St. Louis, MO, USA). MICs were determined by broth microdilution susceptibility testing according to the recommendations of the National Committee for Clinical Laboratory Standards (NCCLS) M7-A5 document [14]. Quality control ranges for MIC testing have been determined earlier by our laboratories [15].
ABT-773 exhibited good in vitro activity against all strains of S. pneumoniae tested regardless of their resistance to erythromycin or penicillin. ABT-773 had the lowest MICs of the two ketolides tested (MIC90, 50.03 mg/l) against erythromycin-resistant strains, but both achieved total inhibition at the same concentration (MIC, 1 mg/l). Similar potency was observed against b-haemolytic streptococci when the MICs of ketolides were compared with those of erythromycin. Both ketolides retained acceptable activity against macrolideresistant b-haemolytic streptococci (MIC90, 50.03 mg/l). All antimicrobials tested against the streptococcus viridans group showed excellent activity and no cross-resistance was observed between ABT-773 and the macrolides. All Corynebacterium spp. (except one strain) were fully resistant to erythromycin and clindamycin using the breakpoint proposed by the NCCLS for non-fastidious microorganisms and staphylococci. None of the ketolides showed cross-resistance with erythromycin or clindamycin (MIC90, 0.25 mg/l) against Corynebacterium spp. or Bacillus spp. The potency of ABT-773 (MIC90, 4 mg/l) was twofold greater than that of telithromycin and erythromycin (MIC90, 8 mg/l) against H. influenzae. Over one-half of the H. influenzae strains had an ABT-773 MIC of 2 mg/l.
4. Conclusion 3. Results The antimicrobial activity of ABT-773 compared with telithromycin and eight other compounds tested against 618 strains of Gram-positive pathogens and 97 strains of H. influenzae is shown in Table 1. ABT-773 showed good activity against erythromycin-susceptible S. aureus (MIC90, 0.06 mg/l) and CoNS (MIC90, 0.06 mg/l). However, erythromycin-resistant staphylococci (MIC90, ]32 mg/l) were not inhibited by clinically relevant ketolide concentrations. The MIC90 of ABT773 (0.06 mg/l) was fourfold lower compared with that of telithromycin (MIC90, 0.25 mg/l) for erythromycinsusceptible staphylococci strains. The vast majority of the erythromycin-resistant strains were also resistant to penicillin, oxacillin, clindamycin and telithromycin, but were inhibited by quinupristin-dalfopristin (MIC90, 1 mg/l) and vancomycin (MIC90, 2 mg/l). ABT-773 showed comparable activity to telithromycin against erythromycin-susceptible enterococci, displaying the best performance of all antimicrobials tested (MIC90, 0.03 mg/l). None of the drugs showed good activity against vancomycin-resistant enterococci; however, quinupristin-dalfopristin was the most potent drug (MIC50, 1 mg/l) against Enterococcus faecium isolates.
The results of the current study indicate that ABT773 has potent in vitro activity against S. pneumoniae, b-haemolytic and viridans group streptococci, even against isolates harbouring the MLSB resistance phenotype. These results are consistent with other studies [8,10]. Similar observations were reported for other ketolides such as telithromycin (RU-66647, HMR 3647) and HMR 3004 (RU 64004) [16–18]. ABT-773 showed poor activity against erythromycin-resistant S. aureus, CoNS- and vancomycin- and erythromycin-resistant enterococci. Very similar activities were achieved by both ketolides against Gram-positive microorganisms and H. influenzae overall, but ABT-773 appeared to be significantly more potent against susceptible strains. ABT-773 may be useful for the treatment of some Gram-positive respiratory tract and skin and soft tissue infections resistant to macrolides, especially those caused by streptococci. Further studies are needed to assess the clinical efficacy of this drug class against erythromycin-resistant pathogen subsets and the Haemophilus spp.
Acknowledgements The co-authors express their gratitude for the input
M.F. Rospide et al. / International Journal of Antimicrobial Agents 17 (2001) 451–455
and support of K. Meyer, M. Beach, M. Erwin and M. Pfaller. This investigation was made possible by funds from the Department of Pathology, University of Iowa College of Medicine, Iowa City, Iowa. Dr Rospide was the recipient of the SENTRY Programme Fellowship for the year 2000 (Bristol-Myers Squibb).
[9]
[10]
References [1] Jones RN, Pfaller MA. Bacterial resistance: a worldwide problem. Diagn Microbiol Infect Dis 1998;31:379 –88. [2] Pfaller MA, Jones RN, Doern GV, Sader HS, Kugler KC, Beach ML. Survey of blood stream infections attributable to gram-positive cocci: frequency of occurrence and antimicrobial susceptibility of isolates collected in 1997 in the United States, Canada, and Latin America from the SENTRY Antimicrobial Surveillance Program. SENTRY Participants Group. Diagn Microbiol Infect Dis 1999;33:283 –97. [3] Jones RN, Pfaller MA. Macrolide and fluoroquinolone (levofloxacin) resistances among Streptococcus pneumoniae strains: significant trends from the SENTRY antimicrobial surveillance program (North America, 1997 – 1999). J Clin Microbiol 2000;38:4298 –9. [4] Schmitz FJ, Verhoef J, Fluit AC. Prevalence of resistance to MLS antibiotics in 20 European university hospitals participating in the European SENTRY surveillance programme. Sentry Participants Group. J Antimicrob Chemother 1999;43:783 – 92. [5] Carbon C, Young L. Ketolides and other derivatives. In: Zinner SH, Young LS, Acar JF, Neu HN, editors. Expanding indications for the new macrolides, azalides and streptogramins. New York, NY: Marcel Dekker Inc, 1997:121 – 3. [6] Bonnefoy A, Girard AM, Agouridas C, Chantot JF. Ketolides lack inducibility properties of MLS(B) resistance phenotype. J Antimicrob Chemother 1997;40:85 –90. [7] Zhong P, Cao Z, Hammond R, et al. Induction of ribosome methylation in MLS-resistant Streptococcus pneumoniae by macrolides and ketolides. Microb Drug Resist 1999;5:183 – 8. [8] Capobianco JO, Cao Z, Shortridge VD, Ma Z, Flamm RK, Zhong P. Studies of the novel ketolide ABT-773: transport, binding to ribosomes and inhibition of protein synthesis in
.
[11]
[12]
[13]
[14]
[15]
[16] [17]
[18]
455
Streptococcus pneumoniae. Antimicrob Agents Chemother 2000;44:1562 – 7. Brueggemann AB, Doern GV, Huynh HK, Wingert EM, Rhomberg PR. In vitro activity of ABT-773, a new ketolide, against recent clinical isolates of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis. Antimicrob Agents Chemother 2000;44:447 – 9. Davies TA, Ednie LM, Hoellman DM, Pankuch GA, Jacobs MR, Appelbaum PC. Antipneumococcal activity of ABT-773 compared to those of 10 other agents. Antimicrob Agents Chemother 2000;44:1894 – 9. Strigl S, Roblin PM, Reznik T, Hammerschlag MR. In vitro activity of ABT 773, a new ketolide antibiotic, against Chlamydia pneumoniae. Antimicrob Agents Chemother 2000;44:1112 –3. Goldstein EJC, Citron DM, Merriam CV, Warren Y, Tyrrell K. Comparative in vitro activities of ABT-773 against aerobic and anaerobic pathogens isolated from skin and soft-tissue animal and human bite wound infections. Antimicrob Agents Chemother 2000;44:2525 – 9. Pendland SL, Prause JL, Neuhauser MM, Boyea N, Hackleman JM, Danziger LH. Invitro activities of a new ketolide, ABT-773, alone and in combination with amoxicillin, metronidazole, or tetracycline against Helicobacter pylori. Antimicrob Agents Chemother 2000;44:2518 – 20. National Committee for Clinical Laboratory Standards. Methods for dilution antimicrobial susceptibility tests for bacteria that grows aerobically. Approved standard M7-A5, 5th ed. Wayne, PA: National Committee for Clinical Laboratory Standards, 2000. Marshall SA, Erwin ME, Jones RN. Determination of MIC quality control ranges for ABT-773, a novel ketolide antimicrobial agent. J Clin Microbiol 2000;38:2462 – 3. Jones RN, Biedenbach DJ. Antimicrobial activity of RU-66647, a new ketolide. Diagn Microbiol Infect Dis 1997;27:7 – 12. Jamjian C, Biedenbach DJ, Jones RN. In vitro evaluation of a novel ketolide antimicrobial agent, RU-64004. Antimicrob Agents Chemother 1997;41:454 – 9. Pankuch GA, Visalli MA, Jacobs MR, Appelbaum PC. Susceptibilities of penicillin- and erythromycin-susceptible and -resistant pneumococci to HMR 3647 (RU 66647), a new ketolide, compared with susceptibilities to 17 other agents. Antimicrob Agents Chemother 1998;42:624 – 30.