METROMDAZOLE COMPARED WITH PENICILLIN IN THE TREATMENT OF ACUTE DENTAL INFECTIONS

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1 British Journal of Oral Surgery 14 ( 1977) METROMDAZOLE COMPARED WITH PENICILLIN IN THE TREATMENT OF ACUTE DENTAL INFECTIONS H. R. INGHAM, M.B.,Ch.B., M.R.C.Path., Dip.Bact.,l F. J. C. HOOD, T.D., B.D.S., L.D.S.,z P. BRADNUM, F.D.S.R.C.S.,j D. THARAGONNET, B.Sc.1 and J. B. SELKON, M.B., Ch.B., M.R.C.Path., D.C.P.1 IPublic Health Laboratory, General Hospital, Newcastle upon Tyne; 2Department of Oral Surgery, University of Newcastle upon Tyne Dental School; 3Dental Department, Newcastle General Hospital, Newcastle upon Tyne Summary. The efficacy of metronidazole in the treatment of acute dental infections was investigated and compared with parenteral penicillin in a controlled trial. All 37 patients in the trial responded satisfactorily and metronidazole appeared to be as effective as parenteral penicillin. A further 24 patients treated with metronidazole also responded satisfactorily. Bacteriological studies of pus obtained from 25 patients revealed the presence of many species of obligate anaerobes. Since metronidazole is only active against obligate anaerobic bacteria it is concluded that these organisms are the important pathogens in acute dental infections. Introduction The bacteriology of acute dental infections has been the subject of many publications most of which have suggested that aerobic or facultative anaerobic bacteria are the main pathogens. The basis for this conclusion has been the sensitivity of many of these organisms to penicillin, an antibiotic which is usually highly effective in the control of acute dental sepsis. Penicillin is, however, also highly active against many species of obligate anaerobes which are present in the oral cavity, and a number of authors have suggested that such organisms might well be of improtance in this condition (Dormer & Babett, 1972; Sims, 1974; Sabiston & Gold, 1974; Sabiston et al., 1976). This hypothesis has been difficult to investigate because of the lack of an agent with antibacterial activity restricted to obligate anaerobes. Recent work indicating that metronidazole fulfils this requirement (Prince et al., 1969; Fuzi & Cusukas, 1970) prompted an investigation of the efficacy of this agent in patients with acute dental infections. In a pilot study of 24 patients treated with 200 mg metronidazole eight hourly all exhibited a rapid and often dramatic response. In view of this it was decided to carry out a blind controlled comparison of metronidazole with penicillin, details of which are reported in this paper, together with preliminary results of bacteriological studies of pus obtained from patients with acute dental infections. Patients and methods Patients Patients presenting with acute dental infections, other than acute ulceromembranous gingivitis (A.U.G.), were allocated at random, using a series of sealed envelopes, to treatment with penicillin G 600 mg plus procaine penicillin 600 mg daily by intramuscular injection or, metronidazole 200 mg eight hourly by mouth, both regimes being continued for three days. When necessary appropriate surgery was performed during or after the course of chemotherapy. All patients were seen at their first and subsequent visits by one of us (F.J.C.H.) who was not aware of the treatment individual patients were receiving. Wherever (Received 9 August 1976; accepted 26 October 1976)

2 Table I METRONIDAZOLE COMPARED WITH PENICILLIN Comparison of the Clinical Features in the Two Treatment Groups 265 Presenting features Penicillin Metronidazole Total Facial swelling Pain Inflammation of gingival mucosa Trismus Presence of pus Cervical adenopathy possible patients were seen daily for three days following their initial visit and the response to treatment assessed by the speed with which the presenting features resolved. These criteria included facial swelling, pain, inflammation of the gingival mucosa lymphadenopathy and more rarely trismus. When possible a specimen of pus was obtained by aspiration from the lesion and a smear was prepared on a glass slide, the remaining material being inoculated into Robertson s cooked meat medium supplemented with 12 per cent lysed horse blood. These specimens were sent to the bacteriology department usually within two hours. Bacteriology Smears were stained by the Gram technique using dilute carbol fuchsin as the counterstain. The cooked meat medium was subcultured on receipt on to the following media. (a) MacConkey agar and 5 per cent defibrinated horse blood agar which were incubated aerobically at 37 C. for two days. (b) Blood agar and blood agar containing nalidixic acid, at a final concentration of 50 pg/ml, as a selective agent. These plates were incubated at 37 C in a mixture of 90 per cent hydrogen and 10 per cent carbon dioxide in an anaerobic jar fitted with a cold catalyst for seven days. After incubation at 37 C for 24 hours, the cooked meat medium was again subcultured in the same manner. A paper disc containing 5 c(g of metronidazole was placed on the anaerobic plates to facilitate the detection of obligate anaerobes. All colonies growing on the anaerobic plates were individually tested for their sensitivity to metronidazole. Those which were sensitive were Gram filmed and further examined to permit a preliminary identification, this being based mainly on antibiotic susceptibility patterns, colonial and microscopical appearances. Results Thirty-seven patients were included in the controlled trial, 19 of whom received penicillin and 18 metronidazole. In the penicillin treatment group, 7 had acute pericoronitis and 12 acute apical infections, the corresponding figures for those patients receiving metronidazole were 5 and 13 respectively. The presenting clinical features in the two groups were comparable (Table I) and there were no treatment failures. A marked clinical improvement was apparent within 2448 hours of commencing

3 266 BRtrtSH JOURNAL OF ORAL SURGERY FIG. la (left). Case I on presentation. FIG. I b (right). Appearance after one day of treatment. FIG. 2a (left). Case 2 on presentation. FIG. 2b (right). Appearance after one day of treatment.

4 Table II METRONIDAZOLE COMPARED WITH PENICILLIN Bacteria Isolated from 25 Patients with Acute Dental Infections 267 Obligate anaerobes No. Aerobes/facuItative anaerobes No. Veillonella 19 Gram-positive cocci 26 Bacteroides melaninogenicus 13 Fusiform* Gram-negative bacilli IO Non-fusiform Gram-negative bacilli 29 Gram-positive bacilli 37 Total 134 Staphylococcus aureas 2 Staphylococcus albrrs 13 Streptococcus viridans IO Non-haemolytic streptococci I1 Neisseria catarrhalis 6 Haemophilus parainfluenzae 4 H. parahaemolyticus 1 H. haemolvticus 1 Diphtheriids 3 Total 51 * Slender bacilli with pointed ends. chemotherapy in both treatment groups and on this basis metronidazole appeared to be as effective as penicillin. The preliminary study, in which the efficacy of metronidazole in acute dental infections was first observed, included 24 patients 8 of which had acute pericoronitis and 16 had apical abscesses; all of these patients responded satisfactorily. Two of these patients were of particular interest because of the severity of their infections and the rapidity of the response to metronidazole and for these reasons brief case reports are given. Case reports Case I A 30-year-old man was referred with a severe cellulitis following the extraction of the second left lower molar under local analgesia the previous day. There was gross swelling of the left side of his face, lower lip, and neck (Fig. la), but he had no difficulty in breathing or swallowing. He looked and felt ill, his temperature was 38.2 C and the white cell count was 22,9OO/cm. He was admitted to hospital and given an initial dose of 800 mg metronidazole orally followed by 600 mg eight hourly. The next morning the swelling had markedly decreased (Fig. I b), he felt better and the temperature had fallen to 37.2 C and the white cell count to 14,9OO/cm, at this stage the dose of metronidazole was reduced to 400 mg eight hourly. During the day he developed a well demarcated erythematous rash in his neck extending from the anterior border of the Sterno-mastoid muscle down to his chest. This rash slowly faded over the next 48 hours, the facial swelling subsided and the patient was discharged home on day 6 on 200 mg metronidazole eight hourly for five days. When seen seven days later his appearance was normal, though there was still a slight fullness in the left submandibular region which had resolved by the following week. Case 2 A 20-year-old girl attended complaining of pain and facial swelling of one day s duration. There was diffuse oedematous swelling of the upper lip and left side of face (Fig. 2a). Intra-oral examination revealed a fluctuant swelling in the labial sulcus over the upper left central incisor, which was very tender to percussion. The root canal was

5 268 BRITISH JOURNAL OF ORAL SURGERY opened and the necrotic pulp removed and, under topical analgesia, an incision was made in the labial sulcus releasing pus. Metronidazole, 200 mg eight hourly wah prescribed. The next day the patient was pain free and her face much less swollen. She could now wear her spectacles which had previously been impossible because of the swelling (Fig. 2b). She continued to improve and within a week was ready for root canat treatment and apicectomy. A total of 25 specimens of pus were obtained from the initial series of patients and those in the controlled trial. Microscopy of these specimens usually revealed a variety of Gram-negative and Gram-positive organisms, including both cocci and bacilli: Borrelia were seen in only three patients and then in very small numbers. The bacteria isolated from these specimens are listed in Table II. Complete identification of the obligate anaerobes has not been carried out at this stage, full details of which will be presented in a further communication. It is noteworthy, however, that obligate anaerobes greatly outnumber aerobes, accounting for 72 per cent of the total bacteria isolated, the average number of different anaerobes per patient being five. Discussion The results of this study have shown that metronidazole is as effective in the treatment of acute dental infections as penicillin, there being no failures of treatment with either agent. The further series of 24 patients treated with metronidazole, but not part of the main study, also all responded satisfactorily. Furthermore, since metronidazole is specifically active only against obligate anaerobic bacteria, these organisms must consequently be regarded as of particular importance in such infections. Metronidazole had been used in the treatment of A.U.G. since 1962 (Shinn), but the only publication, of which we are aware, describing its use in other acute dental infections appeared in 1971 (Dangy rt al.). The latter authors successfully used a combination of metronidazole and spiramycin prophylactically and also therapeutically in 78 patients undergoing dental extractions for a variety of conditions and in 7 patients with perimaxillary infections. It is of interest that this combination has recently been shown to have synergistic action in vitro against Bacteroides fragilis (Salem et al., 1975). The clinical effectiveness of metronidazole in dental infections suggests that it may be a useful alternative to penicillin in the chemotherapy of such conditions, for example when the patient is allergic to penicillin. Perhaps of greater importance is our observation that metronidazole, given orally, was at least as effective as parenteral penicillin. Had the comparison been made with oral pencillin, which is commonly prescribed in dental practice, it is possible that metronidazole would have proved to be the superior agent. Indeed, a number of patients we have treated successfully with metronidazole had failed to respond to oral penicillin prescribed by their dental practitioners. Few side-effects are experienced with metronidazole. Those which have been reported include headache, vomiting, abdominal pain, urticaria, darkening of the urine, a transient and reversible neutropaenia (Lefebvre & Hesseltine, 1965), a toxic psychosis in patients receiving disulfiram (Rothstein & Clancy, 1969) and peripheral neuropathy (Ramsay, 1968; Ingham et al., 1975). The latter complication appears to occur only after administration of metronidazole for a minimum of four weeks and is usually completely reversible. Recently metronidazole has been shown to be carcinogenic in mice (Rustia & Shubik, 1972) but only in doses approximately 12 times the maximum therapeutic dosage in man on the basis of mg/kg body weight, given continuously for the majority of the animals life. Hamilton-Miller and Brumfitt (1976) have questioned the correctness of extrapolating such results to the use of metronidazole in

6 METRONIDAZOLE COMPARED WITH PENICILLIN 269 man on the basis that metronidazole has been in use for 15 years for the treatment of a variety of common conditions and no such carcinogenic effect has been reported. The bacteriological findings in the present study provide evidence in support of those authors who have suggested that obligate anaerobes are of much greater importance in acute dental infections than has previously been believed (Dormer & Babett, 1972; Sabiston & Gold, 1974; Sims, 1974; Sabiston et al., 1976). However, as pointed out by Sabiston et al. (1976) the anaerobic species isolated from dental infections are the same as those found in the mouth in the absence of infection and therefore it has not been possible to prove their pathological role so far. They suggested that the mixed facultative and obligate anaerobic flora may indicate that synergy between these species, is necessary to produce dental sepsis, in particular, the presence of the facultative anaerobic streptococci. Since metronidazole is inactive against facultative anaerobes and yet was as effective as penicillin in the patients in this study. it can be concluded that the obligate anaerobic organisms are the sole pathogens at least once the infection is established. It still remains to determine which obligate anaerobes are the most important pathogens in dental infections. Such a study is in progress in this laboratory. Acknowledgments We are grateful to Mr A. Hind of The Department of Oral Surgery, General Hospital, Newcastle upon Tyne, for permission to publish details of Case 1, to Mr J. A. Furness of the statistical section of The Northern Regional Health Authority and to the photographic departments of The University of Newcastle upon Tyne and The Dental Hospital, Newcastle Area Health Authority (Teaching) and wish to acknowledge financial support from the James Hedley Trust Fund. References Dangy, J., Tosani, B. & Palfer-Sollier, M. (1971). L lnformation Dentaire, 23. Dormer, B. J. & Babett, J. A. (1972). Journal of Oral Surgery, 30, 658. Fuzi, M. & C&as, Z. (1970). Zentralblatt fur Bakteriologie, Parasitenkunde, Infectionskrankheiten und Hygiene (Abteilung l), 213,258. Hamilton-Miller, J. M. T. & Brumfitt, W. (1976). Journal of Antimicrobial Chemotherapy, 2, 5. Ingham, H. R., Selkon, J. B. & Hale, J. H. (1975). Journal of Antimicrobial Chemotherapy, 1, 355. Lefebvre, Y. & Hesseltine, H. C. (1965). Journal of the American Medical Association, 191, 15. Prince, H. N., Grunberg, E., Titsworth, E. & DeLorenzo, W. F. (1969). Applied Microbiology, 18,728. Ramsay, I. D. (1968). British Medical Journal, 4, 206. Rothstein, E. & Clancy, D. D. (1969). New England Journal of Medicine, 280, Rustia, M. & Shubik. P. (1972). Journal of the National Cancer Institute. 48., 721. Sabiston, C. B. & G&d, w. A: (1974). O&l Surgery, 38, 187. Sabiston, C. B., Grigsby, W. R. & Segerstrom, M. T. (1976). Oral Surgery, 41, 430. Salem, A. R., Jackson, D. D. & McFadzean, J. A. (1975). Journal of Antimicrobial Chemotherapy, 1, 382. Shinn, D. L. S. (1962). Lancet, 1, Sims, W. (1974). British Journal of Oral Surgery, 12, 1.

General surgery department of SGMU Lecturer ass. Khilgiyaev R.H. Anaerobic infection. Gas gangrene

General surgery department of SGMU Lecturer ass. Khilgiyaev R.H. Anaerobic infection. Gas gangrene Anaerobic infection Gas gangrene Anaerobic bacteria Anaerobic bacteria are the most numerous inhabitants of the normal gastrointestinal tract, including the mouth Bacteroides fragilis and Clostridium The