Scot. med, J., 1975, 20: 228

ACTIVITY OF CEPHAZOLIN AND OTHER CEPHALOSPORINS AGAINST BACTEROIDES FRAGILIS D. A. Leigh and Kate Simmons Wycombe General Hospital, High Wycombe, Bucks. and Amersham General Hospital, Amersham, Bucks.

Summary. The antibiotic sensitivity of 50 strains of Bacteroides fragilis to four cephalosporin compounds, cephazolin, cephaloridine, cephradine and cephalexin is reported. Cephazolin was found to be the most active, 94 per cent ofstrains being susceptible to blood concentrations achieved on standard dosage, comparative findings with cephaloridine and cephradine were about 50 per cent, and only 22 per cent of strains were inhibited by cephalexin. The importance of infections due to bacteroides is discussed. Although not the treatment of choice, cephazolin, in view of its bacterial activity may be a useful alternative for bacteroides infections but clinical trials are needed to confirm the laboratory results. THE R E is considerable interest In the diagnosis and treatment of anaerobic infections. Following improvements in the collection of specimens for bacteriological examination and in the techniques used in the laboratory, the incidence of isolation has increased and many routine laboratories are commonly reporting anaerobic bacteria in hospital infections. Anaerobic infections most frequently occur following surgery to the gastro-intestinal and uro-genital tracts and the organism most commonly isolated is Bacteroides fragilis (Ledger, 1972; Leigh, 1974). In a study of patients with appendicitis, swabs from the appendix fossa showed bacterial growth in approximately 50 per cent of cases and Bacteroides fragilis was found in over 70 per cent of these specimens (Leigh et al., 1974) and other workers have found similar but lower incidences (Okubadejo et al., 1973; Gilmore et al., 1973). That bacteroides are common pathogens in post-operative infections following gastro-intestinal surgery is not unexpected as this species constitute over 90 per cent of the total bacterial population of the faeces, and in bacteroides bacteraemia most patients have underlying gastrointestinal disease (Gunn, 1956; Gillespie & Guy, 1956; Wilson et al., 1972).The antibiotic sensitivity of anaerobic bacteria is very variable. Whilst species of bacteroides isolated from the mouth show a relatively broad pattern of sensitivity being susceptible to

penicillin, Bacteroides fragilis of intestinal origin is completely resistant to many of the usual substances prescribed for serious infections. There is a high level of resistance to the aminoglycosides including gentamicin and sensitivity to the penicillins can only be achieved by high dosage by the intravenous route of adminstration. There have also been many reports of increasing resistance to certain antibiotics such as tetracyclines (Bodner et al., 1972; Kislak, 1972). At present the antibiotics of choice for bacteroides infections of intestinal origin are clindamycin and metronidazole. However the role of the cephalosporin group of antibiotics has received little attention as until recently even with the most active compound, cephaloridine, concentrations greatly in excess of 25 meg, per ml. are needed to treat over 50 per cent of strains of bacteroides (Kislak, 1972) and these levels are not attainable in the blood on conventional dosage. Increasing the dose or using intravenous administration to get adequate levels increases the likelihood of toxic effects and adds considerably to technical and nursing problems. Many new cephalosporin compounds are now available which provide high blood concentrations on standard dosage and this paper reports the antibiotic sensitivity of a group of 50 strains of Bacteroides fragilis against 4 preparations, cephazolin (Kefzol) and cephaloridine (Ceporin) prescribed systemically, cephalexin

Activity of Cephazolin and other Cephalosporins against Bacteroides FragiIis

(Keflex, Ceporex) an oral compound, and cephradine (Velosef, Eskacef) which can be administered by both routes. Methods The 50 strains of Bacteroides fragilis were isolated from patients with significant hospital infections, usually wound infections following intestinal surgery, but also from patients with bacteraemia, and genital tract infections following surgery. The minimum inhibitory concentrations (MIC) of these strains was carried out by an agar plate assay technique. Doubling dilutions of the 4 cephalosporins were incorporated into blood agar plates, which were inoculated with the strain ofbacteroides in a concentration of 105 organisms per ml. by an applicator. The agar plates were incubated anaerobically using the Gaspak method and were examined after 48 hours. The MIC was read as the concentration of antibiotic where no bacterial growth occurred. Results The distribution of MICs is shown in Table 1. Cephazolin was the more active substance at all concentrations tested up to 25 meg. per ml. and this was most striking at the lower concentrations. At concentrations of 25 meg. per ml., 94 per cent of strains were inhibited by cephazolin, whereas with cephaloridine and cephradine the figures were 84 and 90 per cent respectively. The oral cephalosporin, cephalexin, showed the least activity with only 30 per cent of strains sensitive to this level. All three systemic compounds showed similar numbers of strains resistant to concentrations of 100 meg. per ml. or more but with cephalexin 22 per cent of strains were resistant to this level. The activity of any antibiotic however depends on both the sensitivity of the in-

fecting organism and the concentration attained in the blood on standard dosage and the contrast between the four compounds was more marked when the MIC was compared to the expected blood concentrations on conventional dosage. Following a 500 mg. intramuscular injection of cephazolin the peak blood level is between 35 and 40 meg. per ml. (Gold et al., 1973) and this rises to over 60 meg. per ml. after a 1 g. dose (Hodges & Saslaw, 1973; Nicholas et al., 1973). These levels are inhibitory against 94 per cent of strains of bacteroides. Cephaloridine however produces lower blood concentrations, 15 to 20 meg. per ml. and 35 to 40 meg. per ml. after intramuscular doses of 500 mg. and 1 g. respectively (Currie, 1967; Griffith & Black, 1971) and between 44 and 84 per cent of strains would be susceptible to these levels. Cephradine is unusual in that higher blood levels are achieved after oral therapy than by the systemic route. Following an oral dose of 500 mg. the blood concentration is approximately 15 meg. per ml. and this rises to 30 meg. per ml. after 1 g. However similar intramuscular doses only give levels of 6 and 15 meg. per ml. respectively (Weliky & Zaki, 1973). Therefore at the lower dose level only 14 per cent of strains would be inhibited by the concentration achieved by intramuscular administration although this would rise to 52 per cent with oral treatment and 90 per cent would be susceptible on the higher dose regime. Cephalexin gives a peak serum level of between 12 and 18 meg. per m!. after a dose of 500 mg. (Leigh et al., 1970) and up to 40 meg. per ml. after a 1 g. dose (O'Callaghan et al., 1971). Only 22 and 30 per cent respectively of strains of bacteroides would be inhibited at these levels.

Table I. Minimum inhibitory concentration of 50 strains of Bacteroides tragi/is against four cephalosporins, 1.56 and less Cephazolin Cumulative % Cephaloridine Cumulative % Cephradine Cumulative % Cephalexin Cumulative %

5 (10%) 10 3 (6%) 6 2 (4%) 4 1 (2%) 2

Minimum inhibitory concentration (meg.1m!.) 3.12 6.25 12.5 25 50 9(18%) 28 3 (6%) 12 5 (10%) 14 4 (8%) 10

9 (18 %) 13 (26%) 11 (22%) 94 94 72 46 4 (8%) 5 (10%) 20 (40%) 11 (22%) 84 92 44 34 19 (38 %) 19 (38 %) 2 (4%) 94 90 14 52 4 (8%) 24 (48%) 3 (6%) 3 (6%) 30 78 22 16

100 and more 3 (6%) 100 4 (8%) 100 3 (6%) 100 11 (22%) 100 229

Leigh and Simmons


Many recent reports of the significance of infections due to anaerobic bacteria (Gorbach & Bartlett, 1974; Leigh, 1974) have emphasised the early studies of Vincent (1896), Halle (1898) and Veillon and Zuber (1898). The virulence of these organisms is not in doubt although there is still considerable discussion as to their importance in mixed growths of bacteria isolated from infections. Despite reports that in mixed cultures as good a result can be achieved from prescribing antibiotics specific for anaerobic bacteria as the administration of multiple treatments effective against all organisms isolated, it is still necessary to consider each patient as an individual case when deciding on the best therapy. It is important therefore that antibiotics with a broad spectrum are available for use as a cover against the occasional infection due solely to strains of Enterobacteriaciae. The increase in the isolation rate of bacteroides is undoubtedly due to improvements in collection techniques and the use of selective culture media. It can be startlingly high, from 13 to 60 per cent following major intestinal surgery (Leigh, 1975) and smaller increases have been reported earlier (Hoffman & Gierhake, 1969). Although the outcome of bacteroides infections has been shown to be good other than in the presence of bacteraemia (Wilson et al., 1972), there may be a high incidence of complications (Leigh, 1974) and prolonged period of hospitalisation where effective chemotherapy is not given. Whilst the most active antibiotics against these bacteria are clindamycin and metronidazole, there may be a place for the new preparations of cephalosporins, which give high blood concentrations after systemic therapy. Cephazolin with its bacterial activity against bacteroides, high blood levels even after standard dosage, prolonged half-life and better bile excretion, may be suitable but several precautions should be taken. Satisfactory blood levels will only be maintained for a maximum of 4 to 6 hours and therefore it is necessary that the usual 12-hourly dosage be increased to 6-hourly. In order for the laboratory to provide an accurate assessment of the sensitivity of the infecting organism in 230

relation to the high blood concentrations, the concentration of cephazolin used in the disc testing procedure should be increased to 25 meg. per ml. Most laboratories therefore will have to add an extra disc to their sensitivity testing plate as for the treatment of other bacterial infections it will still be necessary to test with a lower disc concentration for other cephalosporin compounds. The protein binding of cephazolin is high, between 75 and 86 per cent (Nishida et al., 1969; Kirby & Regamey, 1973) and the significance of this in therapy remains to be determined. The antibacterial activity of cephazolin suggests that it may be a useful antibiotic for the treatment of infections due to Bacteroides fragilis although clinical trials are necessary to confirm the laboratory findings. A C K NOW LED GEM E N T s. This work was subsidised by a grant from Eli Lilly and Company Limited. Mrs K Simmons is in receipt of a research grant from Beecham Pharmaceuticals Ltd.


Bodner, S. J., Koenig, M. G., Treanor, L. L., Goodman, J. S. (1972). Antibiotic susceptibility testing of Bacteroides. Antimicrobial Agents and Chemotherapy, 2, 57 Currie, J. P. (1967). Cephaloridine pharmacology and toxicology. Postgraduate Medical Journal, 43 (Supplement) 22 Gillespie, W. A., Guy, J. (1956). Bacteroides in intraabdominal sepsis. Lancet, 1, 1039 Gilmore, O. J. A., Martin, T. D. M., Fletcher, B. N. (1973). Prevention of wound infection after appendicectomy. Lancet, 1, 220 Gold, J. A., McKee, J. J., Ziv, D. S. Experience with cefazoIin: An overall summary of pharmacologic and clinical trials in man. Journal of Infectious Diseases, 128, (Supplement) 415 Gorbach, S. L., Bartlett, J. G. (1974). Anaerobic infections (3 parts). New England Journal of Medicine, 290, 1177, 1237 and 1289 Griffith, R. S., Black, H. R. (1971). Blood, urine and tissue concentrations of the cephalosporin antibiotics in normal subjects. Postgraduate Medical Journal, 47, (Supplement) 32 Gunn, A. A. (1956). Bacteroides septicaemia. Journal ofthe Royal College ofSurgeons of Edinburgh, 2, 41 Halle, J. (1898). Quoted by Gillespie and Guy (1956). Hodges, G. R., Saslaw, S. (1973). Experiences with cefazolin: A new cephalosporin antibiotic. American Journal of Medical Science, 265, 23 Hoffman, K., Gierhake, F. W. (1969). Postoperative infection of wounds by anaerobes. German Medical Monthly, 14, 31

Activity of Cephazolin and other Cephalosporins against Bacteroides Fragilis

Kirby, W. M. M., Regamey, C. (1973). Pharmacokinetics of cefazolin compared with four other cephalosporins. Journal of Infectious Diseases, 128, (Supplement) 341 Kislak, J. W. (1972). The susceptibility of Bacteroides fragilis to 24 antibiotics. Journal of Infectious Diseases, 125, 295 Ledger, W. J. (1972). Infections in obstetrics and gynecology: new developments in treatment. Surgical Clinics of North America, 52, 1447 Leigh, D. A., Faiers, M. c, Brumfitt, W. (1970). Laboratory and clinical studies with cephalexin. Postgraduate Medical Journal, 46 (Supplement) 69 Leigh, D. A. (1974). The clinical importance of infections due to Bacteroides fragilis and the role of antibiotic therapy. British Medical Journal, 3, 225

Nishida, M., Matsubara, T., Murakawa, T., Mine, Y., Yokata, Y., Kuwahara, S., Goto, S. (1969). In vitro and in vivo evaluation of cefazolin: a new cephalosporin C derivative. Antimicrobial Agents and Chemotherapy, 236 O'CalIaghan, C. H., Toothill, J. P. R., Robinson, W. D. (1971). A new approach to the study of serum concentrations of orally administered cephalexin. Journal of Pharmaceutical Pharmacology, 23, 50 Okubadejo, O. A., Green, P. J., Payne, D. J. H. (1973). Bacteroides infections among hospital patients. British Medical Journal, 2, 212 Veillon, A., Zuber, A. (1898). Recherche sur quelques microbes strictement anaerobies, Et leur rMe en pathologie. Archives de Medecine Experimental et d'Anatomie Pathologique, 10, 517

Leigh, D. A., Simmons, K., Norman, E. (1974). Bacterial flora of the appendix fossa and the incidence of wound infection. Journal of Clinical Pathology, 27, 997

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Activity of cephazolin and other cephalosporins against Bacteroides fragilis.

The antibiotic sensitivity of 50 strains of Bacteroides fragilis to four cephalosporin compounds, cephazolin, cephaloridine, cephradine and cephalexin...
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