Correspondence
490
Antagonism between cefoxltin and cefuroxime Sir, While routinely testing Gram-negative rods against the new generation cephalosporins— cefoxitin and cefuroxime, an interesting phenomenon was observed. For organisms like Enterobacter cloacae which are resistant to cefoxitin but sensitive to cefuroxime, it was noticed that these two antibiotics when combined show antagonism. This phenomenon does not always seem to happen with organisms exhibiting similar sensitivity pattern. However, once this is observed with a particular strain the effect is easily reproducible.
Cefoxitin due to its 7a-methoxyl group though resembling cephalosporins belongs to the recently designated cephamycin group (Birnbaum et al., 1978). Cefuroxime on the other hand is a new generation cephalosporin (O'Callaghan et al., 1976). Both are resistant to P-lactamase attack to a considerable extent. Despite the fact that clinically there will not be any need to combine these two antibiotics their in vitro interaction is noteworthy. First of all on a semiconfluent lawn of culture on the Diagnostic Sensitivity Test Agar (Oxoid) with 5 % lysed blood, two discs each of 0-03 mg of cefuroxime and cefoxitin were placed side by side at a distance of 15 mm and then 40 mm apart and the zone of inhibition noted (Plate 1). Then the minimum inhibitory concentrations (MICs) of the individual antibiotics were determined by the agar incorporation technique, the range of concentrations for both the antibiotics ranging between 0-25 mg/1 to 128 mg/1 followed by the checker board titration (Table I). Figure 1 shows that whenever there was antagonism the smooth circular zone diameter was reduced for cefuroxime by cefoxitin and instead it produced an oval zone. Table I shows the results of the checker board titration demonstrating marked antagonism. Antagonism between two antibiotics belonging to the same chemical group has not been reported before though this has been demonstrated by combining penicillin and cephalosporin probably due to competition for cellular binding sites (Acar, Sabbath & Roch, 1975). On the other hand synergy has been noted when two penicillins were combined (Sabbath et al., 1967). The antagonism may be explained by the fact that cefoxitin being highly resistant to P-lactamase is perhaps also a potent inducer of an enzyme which inactivates cefuroxime and therefore, responsible for the reduced zone
Table L Checker board titration of cefoxitin and cefuroxime against a strain of Enterobacter cloacae showing antagonism. Individual MIC cefuroxime, 4 mg/1; cefoxitin, 64 mg/1; + , indicates growth Cefoxitin (mg/I) 128 64 32 16 8 4 2
Na
128
64
32
Cefuroxime (mg/1) 16 8
Nn
Downloaded from http://jac.oxfordjournals.org/ at Pennsylvania State University on May 25, 2015
Phillips, I., Smith, A. & Shannon, K. Antibacterial activity of netilmicin, a new aminoglycoside antibiotic, compared with that of gentamicin. Antimicrobial Agents and Chemotherapy 11: 402-6 (1977). Price, K. E., Defuria, L. D. & Pursiano, T. A. Amikacin, an aminoglycoside with marked activity against antibiotic-resistant clinical isolates. Journal of Infectious Diseases 134: 523961 (1976). Rahal, J. J. Jr., Simberkoff, M. S., Kajan, K. & Moldover, N. M. Bactericidal efficacy of Sen 20569 and amikacin against gentamicin-sensitive and resistant organisms. Antimicrobial Agents and Chemotherapy 9: 595-9 (1976). Reynolds, R. P. & Duncan, I. B. R. Emergence of gentamicin-resistance Klebsielae in a general hospital. Antimicrobial Agents and Chemotherapy 9: 595-99 (1976). Richmond, M. H. & Sykes, R. B. The p-lactamases of Gram-negative bacteria and their possible physiological role. In Advances in Microbial Physiology Vol. 9 (Rose, A. H. & Tempest, P. W. Eds.) Academic Press, London and New York, (1973), pp. 31-85. Seligman, S. J. Frequency of resistance to kanamycin, tobramycin, netilmicin and amikacin in gentamicin-resistant Gram-negative bacteria. Antimicrobial Agents and Chemotherapy 13: 70-73 (1978).
Downloaded from http://jac.oxfordjournals.org/ at Pennsylvania State University on May 25, 2015
Platc",[l. shows antagonism between cefoxitin and cefuroxime against a strain of Enterobacter cloacae. Discs: CXM, cefuroxime; FOX, cefoxitin.
Downloaded from http://jac.oxfordjournals.org/ at Pennsylvania State University on May 25, 2015
Correspondence
491
diameter round it. Also structurally one is a cephalosporin and the other a cephamycin. So even if they are chemically related it may be argued that strictly speaking they do not belong to the same group of antibiotics. Moreover, at this stage no clinical significance can be attached to this interaction because these two antibiotics in question are not going to be used together for treatment.
Chemotherapy 4 {Suppl. B): 15-32 (1978). O'Callaghan, C. H., Sykes, R. B., Ryan, D. M., Foord, R. D. & Muggleton, P. Cefuroxime—a new cephalosporin antibiotic. Journal of Antibiotics 29: 29-37 (1976). Sabbath, L. D., Elder, H. A. & McCall, C. E. Synergistic combinations of penicillins in the treatment of bacteruria. New England Journal of Medicine XTl: 232-8 (1967).
Misuse of antimicrobial agents Sir, In their review article on the misuse of antimicrobial agents, Buckwold & Ronald (1979) inaccurately quote our work (Achong, Hauser & Krusky, 1977a; Achong et al., 19776) as evidence that 'educational programmes have minima], if any, effect on antimicrobial usage in hospitals'. We assessed parenteral therapy with genta-
MICHAEL R. ACHONG St. Joseph's Hospital, Hamilton, Ontario L8N1Y4 Canada References Achong, M. R., Hauser, B. A. & Krusky, J. L. Rational and irrational antibiotic therapy in a Canadian teaching hospital. Canadian Medical Association Journal 116: 256-9 (1977a). Achong, M. R., Wood J., Thcal, H. K. et al. Changes in hospital antibiotic therapy after a quality-of-use study. Lancet ii: 1118-22 (19776). Buckwold, F. J. & Ronald, A. R. Antimicrobial misuse—effects and suggestions for control. Journal of Antimicrobial Chemotherapy 5: 129-36 (1979). Jones, S. R., Pannell, J., Barks, J. etal. The effect of an educational programme upon hospital antibiotic use. American Journal of Medical Science 273: 79-85 (1977).
Downloaded from http://jac.oxfordjournals.org/ at Pennsylvania State University on May 25, 2015
micin, cloxacillin, ampicillin and cephalothin in patients admitted to a surgical, a gynaecological, and a medical ward of a Canadian teaching hospital during the first three months of 1976 and 1977. In 1976, therapy was assessed as irrational in 42%, 50% and 12% of the surgical, gynaecological, and medical patients respectively; the corresponding data for 1977 were 24 %, 25 % 22 % (Achong et al., \911a, b). Our initial survey identified prolonged prophyB. CHATTOPADHYAY lactic antibiotic as a major cause for irrational I. HALL antimicrobial therapy on non-medical wards. Public Health Laboratory and The more rational therapy in 1977 was mainly Department of Microbiology, due to a shorter duration of prophylactic Whipps Cross Hospital, London Ell 1NR, therapy. Contrary to the statement made by England Buckwold and Ronald, I think that our studies demonstrate the potential benefit of audits of References antimicrobial therapy on subsequent prescribAcar, J. R., Sabbath, L. D. & Roch, P. A. ing patterns. I would agree that merely recordAntagonism of the antibacterial action of some ing less-than-ideal prescribing practices does penicillins by other penicillins and cephalo- not guarantee changes in prescribing patterns sporins. Journal of Clinical Investigation 55: (Jones et al., 1977). However, our success in 446-53 (1975). improving prophylactic antimicrobial therapy Bimbaum, J., Stapley, E. O., Maier, A. K., on the non-medical wards of our hospital may Wallick, H., Hendlin, D. & Woodruff, H. B. be related to the fact that we clearly identified Cefoxitin, a semi-synthetic cephamycin: a microbiological review. Journal of Antimicrobial one aspect of therapy that was indefensible.
490
Antagonism between cefoxltin and cefuroxime Sir, While routinely testing Gram-negative rods against the new generation cephalosporins— cefoxitin and cefuroxime, an interesting phenomenon was observed. For organisms like Enterobacter cloacae which are resistant to cefoxitin but sensitive to cefuroxime, it was noticed that these two antibiotics when combined show antagonism. This phenomenon does not always seem to happen with organisms exhibiting similar sensitivity pattern. However, once this is observed with a particular strain the effect is easily reproducible.
Cefoxitin due to its 7a-methoxyl group though resembling cephalosporins belongs to the recently designated cephamycin group (Birnbaum et al., 1978). Cefuroxime on the other hand is a new generation cephalosporin (O'Callaghan et al., 1976). Both are resistant to P-lactamase attack to a considerable extent. Despite the fact that clinically there will not be any need to combine these two antibiotics their in vitro interaction is noteworthy. First of all on a semiconfluent lawn of culture on the Diagnostic Sensitivity Test Agar (Oxoid) with 5 % lysed blood, two discs each of 0-03 mg of cefuroxime and cefoxitin were placed side by side at a distance of 15 mm and then 40 mm apart and the zone of inhibition noted (Plate 1). Then the minimum inhibitory concentrations (MICs) of the individual antibiotics were determined by the agar incorporation technique, the range of concentrations for both the antibiotics ranging between 0-25 mg/1 to 128 mg/1 followed by the checker board titration (Table I). Figure 1 shows that whenever there was antagonism the smooth circular zone diameter was reduced for cefuroxime by cefoxitin and instead it produced an oval zone. Table I shows the results of the checker board titration demonstrating marked antagonism. Antagonism between two antibiotics belonging to the same chemical group has not been reported before though this has been demonstrated by combining penicillin and cephalosporin probably due to competition for cellular binding sites (Acar, Sabbath & Roch, 1975). On the other hand synergy has been noted when two penicillins were combined (Sabbath et al., 1967). The antagonism may be explained by the fact that cefoxitin being highly resistant to P-lactamase is perhaps also a potent inducer of an enzyme which inactivates cefuroxime and therefore, responsible for the reduced zone
Table L Checker board titration of cefoxitin and cefuroxime against a strain of Enterobacter cloacae showing antagonism. Individual MIC cefuroxime, 4 mg/1; cefoxitin, 64 mg/1; + , indicates growth Cefoxitin (mg/I) 128 64 32 16 8 4 2
Na
128
64
32
Cefuroxime (mg/1) 16 8
Nn
Downloaded from http://jac.oxfordjournals.org/ at Pennsylvania State University on May 25, 2015
Phillips, I., Smith, A. & Shannon, K. Antibacterial activity of netilmicin, a new aminoglycoside antibiotic, compared with that of gentamicin. Antimicrobial Agents and Chemotherapy 11: 402-6 (1977). Price, K. E., Defuria, L. D. & Pursiano, T. A. Amikacin, an aminoglycoside with marked activity against antibiotic-resistant clinical isolates. Journal of Infectious Diseases 134: 523961 (1976). Rahal, J. J. Jr., Simberkoff, M. S., Kajan, K. & Moldover, N. M. Bactericidal efficacy of Sen 20569 and amikacin against gentamicin-sensitive and resistant organisms. Antimicrobial Agents and Chemotherapy 9: 595-9 (1976). Reynolds, R. P. & Duncan, I. B. R. Emergence of gentamicin-resistance Klebsielae in a general hospital. Antimicrobial Agents and Chemotherapy 9: 595-99 (1976). Richmond, M. H. & Sykes, R. B. The p-lactamases of Gram-negative bacteria and their possible physiological role. In Advances in Microbial Physiology Vol. 9 (Rose, A. H. & Tempest, P. W. Eds.) Academic Press, London and New York, (1973), pp. 31-85. Seligman, S. J. Frequency of resistance to kanamycin, tobramycin, netilmicin and amikacin in gentamicin-resistant Gram-negative bacteria. Antimicrobial Agents and Chemotherapy 13: 70-73 (1978).
Downloaded from http://jac.oxfordjournals.org/ at Pennsylvania State University on May 25, 2015
Platc",[l. shows antagonism between cefoxitin and cefuroxime against a strain of Enterobacter cloacae. Discs: CXM, cefuroxime; FOX, cefoxitin.
Downloaded from http://jac.oxfordjournals.org/ at Pennsylvania State University on May 25, 2015
Correspondence
491
diameter round it. Also structurally one is a cephalosporin and the other a cephamycin. So even if they are chemically related it may be argued that strictly speaking they do not belong to the same group of antibiotics. Moreover, at this stage no clinical significance can be attached to this interaction because these two antibiotics in question are not going to be used together for treatment.
Chemotherapy 4 {Suppl. B): 15-32 (1978). O'Callaghan, C. H., Sykes, R. B., Ryan, D. M., Foord, R. D. & Muggleton, P. Cefuroxime—a new cephalosporin antibiotic. Journal of Antibiotics 29: 29-37 (1976). Sabbath, L. D., Elder, H. A. & McCall, C. E. Synergistic combinations of penicillins in the treatment of bacteruria. New England Journal of Medicine XTl: 232-8 (1967).
Misuse of antimicrobial agents Sir, In their review article on the misuse of antimicrobial agents, Buckwold & Ronald (1979) inaccurately quote our work (Achong, Hauser & Krusky, 1977a; Achong et al., 19776) as evidence that 'educational programmes have minima], if any, effect on antimicrobial usage in hospitals'. We assessed parenteral therapy with genta-
MICHAEL R. ACHONG St. Joseph's Hospital, Hamilton, Ontario L8N1Y4 Canada References Achong, M. R., Hauser, B. A. & Krusky, J. L. Rational and irrational antibiotic therapy in a Canadian teaching hospital. Canadian Medical Association Journal 116: 256-9 (1977a). Achong, M. R., Wood J., Thcal, H. K. et al. Changes in hospital antibiotic therapy after a quality-of-use study. Lancet ii: 1118-22 (19776). Buckwold, F. J. & Ronald, A. R. Antimicrobial misuse—effects and suggestions for control. Journal of Antimicrobial Chemotherapy 5: 129-36 (1979). Jones, S. R., Pannell, J., Barks, J. etal. The effect of an educational programme upon hospital antibiotic use. American Journal of Medical Science 273: 79-85 (1977).
Downloaded from http://jac.oxfordjournals.org/ at Pennsylvania State University on May 25, 2015
micin, cloxacillin, ampicillin and cephalothin in patients admitted to a surgical, a gynaecological, and a medical ward of a Canadian teaching hospital during the first three months of 1976 and 1977. In 1976, therapy was assessed as irrational in 42%, 50% and 12% of the surgical, gynaecological, and medical patients respectively; the corresponding data for 1977 were 24 %, 25 % 22 % (Achong et al., \911a, b). Our initial survey identified prolonged prophyB. CHATTOPADHYAY lactic antibiotic as a major cause for irrational I. HALL antimicrobial therapy on non-medical wards. Public Health Laboratory and The more rational therapy in 1977 was mainly Department of Microbiology, due to a shorter duration of prophylactic Whipps Cross Hospital, London Ell 1NR, therapy. Contrary to the statement made by England Buckwold and Ronald, I think that our studies demonstrate the potential benefit of audits of References antimicrobial therapy on subsequent prescribAcar, J. R., Sabbath, L. D. & Roch, P. A. ing patterns. I would agree that merely recordAntagonism of the antibacterial action of some ing less-than-ideal prescribing practices does penicillins by other penicillins and cephalo- not guarantee changes in prescribing patterns sporins. Journal of Clinical Investigation 55: (Jones et al., 1977). However, our success in 446-53 (1975). improving prophylactic antimicrobial therapy Bimbaum, J., Stapley, E. O., Maier, A. K., on the non-medical wards of our hospital may Wallick, H., Hendlin, D. & Woodruff, H. B. be related to the fact that we clearly identified Cefoxitin, a semi-synthetic cephamycin: a microbiological review. Journal of Antimicrobial one aspect of therapy that was indefensible.
