Journal of Antimicrobial Chemotherapy (1990) 25, Suppl. A, 15-18
In-vitro activity of azithromycin against various Gram-negative bacilli and anaerobic bacteria
Hopital Saint Joseph, 7 rue Pierre Larousse, 75015 Paris, France The MICs of azithromycin, crythromycin and roxithromycin were determined (by an agar dilution method) for 65 strains of Gram-negative bacteria responsible for endocarditis and gastrointestinal infections, for 20 strains of non-fermenting Gramnegative bacteria and for 16 strains of anaerobic bacteria. The MICs of azithromycin were up to eight times lower than those of erythromycin and (except in the case of Flavobacterium spp.) up to 16 times lower than those of roxithromycin. Azithromycin was ineffective against strains showing a high degree of erythromycin resistance. Introduction
Azithromycin (CP-62,993; Pfizer Central Research) is a new macrolide antibiotic, the first of a novel subclass referred to as the azalides (Bright etal., 1988). This agent has been shown to have unusual pharmacokinetic properties, achieving rapid and sustained high tissue concentrations with oral dosing (Girard etal., 1987). Azithromycin has already been shown to have in-vitro activity against a wide range of pathogens (Retsema et al., 1987) and to be more effective than other macrolide antibiotics against many common pathogens (Barry, Jones & Thornsberry, 1988; Fernandes & Hardy, 1988; Hardy etal., 1988). The aim of this investigation was to add to the data on azithromycin by establishing its activity against Gram-negative bacilli responsible for endocarditis and various gastrointestinal infections, non-fermenting Gram-negative bacilli, and anaerobes. Materials and methods Bacterial strains
Table I lists the bacterial strains included in this study. A total of 101 unselected consecutive isolates of these species from clinical specimens at St Joseph Hospital, Paris, were tested. Bacteria were identified by standard methods (Lennette et al., 1980). Antimicrobial agents Azithromycin was obtained from Pfizer Central Research (Sandwich, UK), erythromycin from Abbott Laboratories (France), and roxithromycin from Roussel Laboratories (France). The agents were stored at 4°C and solutions were prepared on the day of use according to the manufacturers' instructions. 15 0305-7453/90/25A015+04 $02.00/0
© 1990 The British Society for Antimicrobial Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on February 24, 2015
M. D. Kitris, F. W. Gold-stein, M. Miegi and J. F. Acar
16
M. D. Khzfa et aL
Table L Activity of azithromycin (A), erythromycin (E) and roxithromycin (R) against 101 bacterial isolates Organism Gram-negative bacilli causing endocarditis Actinobactilus actinomycetemcomltans
No. of strains
3 2
Eikmella corrodent
4
Haemophilia aphrophilus
2
Pasteurella spp.
6
A E R A E R A E R A E R A R
(K)3-l 003-8 006-32 1 8 32 025-8 012-8 006-32 1-4 4-8 16-32 1-4 2-16 2-8
A E R A E R A E R A E R A E R A E R A E R A E R
05-4 2-16 32-128 012-128 05-128 1-128 1-2 1-2 4 05-2 16-32 32 2-4 32-128 5*256 05-4 16-64 J»256 012-1 012-4 012-32 2-64 8-32 32-128
A E R A E R
>256 >256 £256 1-64 16-64 128
E Gastrointestinal pathogens Aeromonas spp. Camp, jejuni
6 10
Cl. perfringens
4
Escherichia coli (enterotoxigenic)
4
Salmonella spp.
7
Shigella spp.
7
Mobiluncus spp.
4
Yersinia spp.
6
Non-fermenting Gram-negative bacilli Achromobacter spp. Acinetobacter spp.
3 7
MIC range (mg/1)
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on February 24, 2015
Cardiobacterium hominis
Agent
In-vitro activity
17
Table L contd No. of strains
Organism Bordetella bronchiseptica Flavobacterium spp.
Peptococcus spp. Peptostreptococcus spp.
MIC range (mg/I)
A E R A E R
1-16 8-32 4-8 0-5-128 1-128 1-8
A E R A E R A E R
0-5-64 003-64 0-12-64 0-5-128 1-128 4-128 0O3-4 0O3-4
Minimum inhibitory concentrations MICs were determined by a dilution technique on Mueller-Hinton agar to which 5% horse blood was added for those strains requiring it. A final inoculum of 107cfu/ml was prepared by dilution of an 18-hour broth culture, and inoculated with a multiplepoint Steers inoculator, delivering a 6-7 mm diameter spot (103-10*cfu/spot). Plates were incubated for 18 h at 37°C. Anaerobic bacteria and Campylobacter strains were incubated in the atmospheres produced by GasPak and Campylobacter kits (Oxoid), respectively. The MIC was recorded as the lowest concentration inhibiting macroscopic growth of each strain under investigation. Results and discussion Table I lists the MICs of the three agents for all the strains tested. When these were considered together the MIQQS of azithromycin, erythromycin and roxithromycin were 2, 16 and 32mg/l, respectively. The MIG^s of azithromycin for endocarditis-causing pathogens were 1-8 times lower than those of erythromycin and 2-32 times lower than those of roxithromycin. Since azithromycin has bactericidal activity against some bacterial species (Retsema etal., 1987), it might be considered for the treatment of bacterial endocarditis caused by less common pathogens such as those tested in this study, although bactericidal activity has not been demonstrated in the present investigation. For most gastrointestinal pathogens, azithromycin MICs were ^ 4 mg/1 and considerably lower than those of erythromycin, while roxithromycin showed the least activity. The exceptions were Clostridium perfringens, against which azithromycin and erythromycin showed similar activity, and Camp, jejuni, the isolates of which included macrolide-resistant strains, with azithromycin MICs of 64-128 mg/1. The findings are similar to the results published by Retsema etal. (1987). The MICs have to be
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on February 24, 2015
Anaerobic bacteria Bacteroides fragilis
Agent
18
M. D. Kltzb et aL
considered in terms of the high concentrations of macrolides that are found in the gastrointestinal tract. All three drugs had poor activity against most non-fermenting Gram-negative bacilli, and against anaerobes (except some Peptostreptococcus strains). Among the isolates tested, all high-level erythrpmycin-resistant strains were also resistant to roxithromycin and azithromycin. These data indicate that for most bacterial species tested, azithromycin was 4- to 16fold more effective than erythromycin and roxithromycin and warrant further in-vitro studies, together with clinical trials.
Barry, A. L., Jones, R. N. & Thornsberry, C. (1988). In vitro activities of azithromycin (CP-62,993), clarithromycin (A-56,268; TE-031), erythromycin, roxithromycin, and dindamycin. Antimicrobial Agents and Chemotherapy 32, 752-4. Bright, G. M., Nagcl, A. A., Bordner, J., Desai, K. A., Dibrino, J. N., Nowakowska J. etal. (1988). Synthesis, in vitro and in vivo activity of novel 9-deoxc-9a-aza-9a-homoerythromycin A derivatives; a new class of macrolide antibiotics, the azalides. Journal of Antibiotics 41, 1029-47. Fernandes, P. B. & Hardy, D. J. (1988). Comparative in vitro potencies of nine new macrolides. Drugs Under Experimental and Clinical Research 14, 445-51. Girard, A. E., Girard, D., English, A. R., Gootz, T. D., Cimochowski, C. R., Faiella, J. A. et al. (1987). Pharmacokinetic and in vivo studies with azithromycin (CP-62,993), a new macrolide with an extended half-life and excellent tissue distribution. Antimicrobial Agents and Chemotherapy 31, 1948-54. Hardy, D. J., Hensey, D. M., Beyer, J. M., Vojtko, C , McDonald, E.J. & Fernandes, P. B. (1988). Comparative in vitro activities of new 14-, 15-, and 16-membered macrolides. Antimicrobial Agents and Chemotherapy 32, 1710-9. Lennette, E. H., Balows, A., Mausler, W. J. & Truant, J. P. (Eds) (1980). Manual of Clinical Microbiology. American Society for Microbiology, Washington, DC. Retsema, J., Girard, A., Shelkly, W., Manousos, M., Anderson, M., Bright, G. etal. (1987). Spectrum and mode of action of azithromycin (CP-62,993), a new 15-membered-ring macrolides with improved potency against Gram-negative organisms. Antimicrobial Agents and Chemotherapy 31, 1939-47.
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on February 24, 2015
References
In-vitro activity of azithromycin against various Gram-negative bacilli and anaerobic bacteria
Hopital Saint Joseph, 7 rue Pierre Larousse, 75015 Paris, France The MICs of azithromycin, crythromycin and roxithromycin were determined (by an agar dilution method) for 65 strains of Gram-negative bacteria responsible for endocarditis and gastrointestinal infections, for 20 strains of non-fermenting Gramnegative bacteria and for 16 strains of anaerobic bacteria. The MICs of azithromycin were up to eight times lower than those of erythromycin and (except in the case of Flavobacterium spp.) up to 16 times lower than those of roxithromycin. Azithromycin was ineffective against strains showing a high degree of erythromycin resistance. Introduction
Azithromycin (CP-62,993; Pfizer Central Research) is a new macrolide antibiotic, the first of a novel subclass referred to as the azalides (Bright etal., 1988). This agent has been shown to have unusual pharmacokinetic properties, achieving rapid and sustained high tissue concentrations with oral dosing (Girard etal., 1987). Azithromycin has already been shown to have in-vitro activity against a wide range of pathogens (Retsema et al., 1987) and to be more effective than other macrolide antibiotics against many common pathogens (Barry, Jones & Thornsberry, 1988; Fernandes & Hardy, 1988; Hardy etal., 1988). The aim of this investigation was to add to the data on azithromycin by establishing its activity against Gram-negative bacilli responsible for endocarditis and various gastrointestinal infections, non-fermenting Gram-negative bacilli, and anaerobes. Materials and methods Bacterial strains
Table I lists the bacterial strains included in this study. A total of 101 unselected consecutive isolates of these species from clinical specimens at St Joseph Hospital, Paris, were tested. Bacteria were identified by standard methods (Lennette et al., 1980). Antimicrobial agents Azithromycin was obtained from Pfizer Central Research (Sandwich, UK), erythromycin from Abbott Laboratories (France), and roxithromycin from Roussel Laboratories (France). The agents were stored at 4°C and solutions were prepared on the day of use according to the manufacturers' instructions. 15 0305-7453/90/25A015+04 $02.00/0
© 1990 The British Society for Antimicrobial Chemotherapy
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on February 24, 2015
M. D. Kitris, F. W. Gold-stein, M. Miegi and J. F. Acar
16
M. D. Khzfa et aL
Table L Activity of azithromycin (A), erythromycin (E) and roxithromycin (R) against 101 bacterial isolates Organism Gram-negative bacilli causing endocarditis Actinobactilus actinomycetemcomltans
No. of strains
3 2
Eikmella corrodent
4
Haemophilia aphrophilus
2
Pasteurella spp.
6
A E R A E R A E R A E R A R
(K)3-l 003-8 006-32 1 8 32 025-8 012-8 006-32 1-4 4-8 16-32 1-4 2-16 2-8
A E R A E R A E R A E R A E R A E R A E R A E R
05-4 2-16 32-128 012-128 05-128 1-128 1-2 1-2 4 05-2 16-32 32 2-4 32-128 5*256 05-4 16-64 J»256 012-1 012-4 012-32 2-64 8-32 32-128
A E R A E R
>256 >256 £256 1-64 16-64 128
E Gastrointestinal pathogens Aeromonas spp. Camp, jejuni
6 10
Cl. perfringens
4
Escherichia coli (enterotoxigenic)
4
Salmonella spp.
7
Shigella spp.
7
Mobiluncus spp.
4
Yersinia spp.
6
Non-fermenting Gram-negative bacilli Achromobacter spp. Acinetobacter spp.
3 7
MIC range (mg/1)
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on February 24, 2015
Cardiobacterium hominis
Agent
In-vitro activity
17
Table L contd No. of strains
Organism Bordetella bronchiseptica Flavobacterium spp.
Peptococcus spp. Peptostreptococcus spp.
MIC range (mg/I)
A E R A E R
1-16 8-32 4-8 0-5-128 1-128 1-8
A E R A E R A E R
0-5-64 003-64 0-12-64 0-5-128 1-128 4-128 0O3-4 0O3-4
Minimum inhibitory concentrations MICs were determined by a dilution technique on Mueller-Hinton agar to which 5% horse blood was added for those strains requiring it. A final inoculum of 107cfu/ml was prepared by dilution of an 18-hour broth culture, and inoculated with a multiplepoint Steers inoculator, delivering a 6-7 mm diameter spot (103-10*cfu/spot). Plates were incubated for 18 h at 37°C. Anaerobic bacteria and Campylobacter strains were incubated in the atmospheres produced by GasPak and Campylobacter kits (Oxoid), respectively. The MIC was recorded as the lowest concentration inhibiting macroscopic growth of each strain under investigation. Results and discussion Table I lists the MICs of the three agents for all the strains tested. When these were considered together the MIQQS of azithromycin, erythromycin and roxithromycin were 2, 16 and 32mg/l, respectively. The MIG^s of azithromycin for endocarditis-causing pathogens were 1-8 times lower than those of erythromycin and 2-32 times lower than those of roxithromycin. Since azithromycin has bactericidal activity against some bacterial species (Retsema etal., 1987), it might be considered for the treatment of bacterial endocarditis caused by less common pathogens such as those tested in this study, although bactericidal activity has not been demonstrated in the present investigation. For most gastrointestinal pathogens, azithromycin MICs were ^ 4 mg/1 and considerably lower than those of erythromycin, while roxithromycin showed the least activity. The exceptions were Clostridium perfringens, against which azithromycin and erythromycin showed similar activity, and Camp, jejuni, the isolates of which included macrolide-resistant strains, with azithromycin MICs of 64-128 mg/1. The findings are similar to the results published by Retsema etal. (1987). The MICs have to be
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on February 24, 2015
Anaerobic bacteria Bacteroides fragilis
Agent
18
M. D. Kltzb et aL
considered in terms of the high concentrations of macrolides that are found in the gastrointestinal tract. All three drugs had poor activity against most non-fermenting Gram-negative bacilli, and against anaerobes (except some Peptostreptococcus strains). Among the isolates tested, all high-level erythrpmycin-resistant strains were also resistant to roxithromycin and azithromycin. These data indicate that for most bacterial species tested, azithromycin was 4- to 16fold more effective than erythromycin and roxithromycin and warrant further in-vitro studies, together with clinical trials.
Barry, A. L., Jones, R. N. & Thornsberry, C. (1988). In vitro activities of azithromycin (CP-62,993), clarithromycin (A-56,268; TE-031), erythromycin, roxithromycin, and dindamycin. Antimicrobial Agents and Chemotherapy 32, 752-4. Bright, G. M., Nagcl, A. A., Bordner, J., Desai, K. A., Dibrino, J. N., Nowakowska J. etal. (1988). Synthesis, in vitro and in vivo activity of novel 9-deoxc-9a-aza-9a-homoerythromycin A derivatives; a new class of macrolide antibiotics, the azalides. Journal of Antibiotics 41, 1029-47. Fernandes, P. B. & Hardy, D. J. (1988). Comparative in vitro potencies of nine new macrolides. Drugs Under Experimental and Clinical Research 14, 445-51. Girard, A. E., Girard, D., English, A. R., Gootz, T. D., Cimochowski, C. R., Faiella, J. A. et al. (1987). Pharmacokinetic and in vivo studies with azithromycin (CP-62,993), a new macrolide with an extended half-life and excellent tissue distribution. Antimicrobial Agents and Chemotherapy 31, 1948-54. Hardy, D. J., Hensey, D. M., Beyer, J. M., Vojtko, C , McDonald, E.J. & Fernandes, P. B. (1988). Comparative in vitro activities of new 14-, 15-, and 16-membered macrolides. Antimicrobial Agents and Chemotherapy 32, 1710-9. Lennette, E. H., Balows, A., Mausler, W. J. & Truant, J. P. (Eds) (1980). Manual of Clinical Microbiology. American Society for Microbiology, Washington, DC. Retsema, J., Girard, A., Shelkly, W., Manousos, M., Anderson, M., Bright, G. etal. (1987). Spectrum and mode of action of azithromycin (CP-62,993), a new 15-membered-ring macrolides with improved potency against Gram-negative organisms. Antimicrobial Agents and Chemotherapy 31, 1939-47.
Downloaded from http://jac.oxfordjournals.org/ at University of California, San Francisco on February 24, 2015
References
