Metronidazole in Anaerobic Infections: A Review of its Activity, Pharmacokinetics and Therapeutic Use
- 66 Downloads
Synopsis:Metronidazole1which has been widely used for many years in the treatment of trichomoniasis, amoebiasis and giardiasis, has recently been shown to be active against anaerobic bacteria. Serum, cerebrospinal fluid and tissue concentrations bactericidal for Bacteroides species are attained after usual dosages given orally or intravenously or higher dosages given rectally (suppository). Prospective studies have demonstrated that the addition of metronidazole to regimens for pre-operative bowel preparation, decreases the frequency of postoperative infection and eliminates anaerobic infection. Similarly, anaerobic infection after acute appendicectomy or hysterectomy has been virtually eliminated by metronidazole given before and up to 1 week after surgery. Metronidazole has been successfully used in the treatment of anaerobic infections of the chest, head, gastrointestinal and female genitourinary tract, and of anaerobic septicaemia and bacteraemia.
Metronidazole is the most active agent available against obligate anaerobes and is likely to be of major value in the treatment of serious infections due to these organisms. Although the absence of formal comparative trials in many areas of use makes it difficult to clearly state the relative therapeutic efficacy of metronidazole, compared with other drugs such as clindamycin, chloramphenicol or penicillin, it is nevertheless a very effective agent in the treatment and prevention of anaerobic infections.
Antimicrobial Activity: Metronidazole, as well as other nitroimidazoles such as tinidazole, is active in vitro against obligate anaerobes, but has no clinically relevant activity against facultative anaerobes, obligate aerobes or microaerophilic bacteria other than Campylobacter fetus and H. (Corynebacterium) vaginalis. At concentrations readily attained in serum after oral, rectal or intravenous administration, metronidazole is active against Bacteroides fragilis, and B. melaninogenicus, Fusobacterium sp, Clostridium perfringens and other Clostridium species. However, it is generally less active against non-sporeforming Gram-positive bacilli such as Actinomyces sp, Propionibacterium sp, Bifidobacterium sp and Eubacterium sp; it is also somewhat less active against Gram-positive cocci (Peptostreptococcus and Peptococcus sp), but the less sensitive strains are usually not obligate anaerobes. Against susceptible organisms, metronidazole is generally bactericidal at concentrations equal to or slightly higher than the minimum inhibitory concentration.
The precise mode of action of metronidazole is not clear, but it appears that after entering the cell, the drug is reduced by some means and binds to desoxyribonucleic acid. Only susceptible bacteria appear to be capable of metabolising the drug.
Toxicology Studies: The toxicity of metronidazole during long term administration varies between strains of mice and different animal species, the dog exhibiting neurological disturbances not observed with other animal species. High oral dosages caused weight loss and testicular atrophy in one strain of mice and in rats, whilst intravenous metronidazole did not influence the rate of weight gain in rats or produce any significant changes in blood pressure or in haematological or biochemical values. Histological liver changes without associated changes in serum enzyme levels occurred in monkeys given high dosages.
Dosages of up to 1g/kg daily for 5 weeks did not produce a dominant lethal effect in the mouse. An increased incidence of lung tumours and malignant lymphoma have been reported in Swiss mice studied at one laboratory, but not in Sprague-Dawley rats or hamsters studied by other investigators. Further studies have failed to demonstrate that metronidazole induces unscheduled DNA synthesis or is mutagenic in male mice by the heritable translocation procedure.
A recent retrospective study conducted by the Mayo Clinic showed that the incidence of cancer in women who received metronidazole for T. vaginalis infections was not significantly different from that expected in that population, based on the observed number of cases in a larger population.
Pharmacokinetics: Metronidazole appears to be readily absorbed after oral administration. Peak serum concentrations are attained 1 to 3 hours after a single dose, but reported serum levels vary according to the assay method used. Microbiological assay has the advantage of indicating therapeutic activity but does not differentiate between the parent substance and some of its metabolites. After a single 250mg dose, peak serum concentration is about 5μg/ml, determined using GLC. The bioavailability of metronidazole does not appear to be significantly decreased by concomitant food ingestion.
Distribution studies in healthy human subjects and in patients, indicate that metronidazole readily penetrates into the cerebrospinal fluid and attains therapeutic concentrations in pus from cerebral abscesses and in empyema fluid. Metronidazole has a high apparent volume of distribution and is only slightly bound to serum proteins.
Metronidazole is eliminated in man largely by metabolism, resulting from side-chain oxidation, hydroxylation or conjugation of the parent compound. Over a period of 24 hours after oral administration of metronidazole, urinary recovery of total nitroderivatives accounts for 35 to 65 % of the dose when determined by chemical assay and for 15 to 20 % when bioassay is used. In the non-obstructed biliary tract, metronidazole is present in hepatic bile in concentrations similar to those found in serum and is concentrated in the normal gallbladder. The reported elimination half-life has varied between 6.2 and 11.5 hours in healthy subjects. The area under the serum concentration-time curve did not differ significantly in patients with normal or impaired renal function.
Metronidazole in Anaerobic Infections: Anaerobes are responsible for a variety of types of infection and are frequently found in clinical specimens from abdominal abscesses, peritonitis, thoracic empyema and in female genital tract infections. Although the distinction between isolates that are commensals or contaminants and those which are true pathogens may sometimes be difficult to make from routine specimens, it is established that anaerobes play a major role in postoperative infections related to the abdomen. Bacteroides species are frequently isolated from abdominal abscesses and wounds and in mixed culture in infections related to loss of integrity of the bowel mucosa and surgery of the female genital tract.
Metronidazole administered orally, rectally or intravenously has been successfully used to treat a wide range of intra-abdominal anaerobic infections, anaerobic infections resulting from surgery and trauma of the female genital tract, anaerobic chest infections, anaerobic infections of the head (brain abscess), peridontal infections, otitis media, infections of the bones and joints, and a few cases of anaerobic bacteraemia and endocarditis. In some instances the efficacy of metronidazole has been difficult to determine as it has been used in association with antibacterial agents active against aerobic and anaerobic bacteria. However, metronidazole has been effective in the treatment of septicaemia caused by anaerobic bacteria resistant to chloramphenicol and clindamycin, bacteraemia which has failed to respond to clindamycin, and endocarditis which has failed to respond to high dosages of benzylpenicillin plus streptomycin.
Metronidazole has been shown to be effective in anaerobic chest infections and anaerobic soft tissue pelvic infections in obstetrics and gynaecology, but it has not been compared in formal therapeutic trials with currently employed antimicrobial agents. Of the several agents available for the treatment of anaerobic pleuropulmonary infections, penicillin is the drug of choice, other than for B. fragilis infection. Whilst some authorities consider clindamycin to be the alternative of choice in penicillin sensitive patients because of the extent of documentation, others would prefer to use metronidazole.
In deep seated anaerobic pelvic infections metronidazole would be considered by workers in some parts of the world to be the drug of choice in preference to chloramphenicol and clindamycin, the current agents of choice in other countries.
As metronidazole penetrates readily into the CSF it is considered by some to be the agent of choice in place of chloramphenicol in the treatment of anaerobic meningitis, and on the basis of present data, it appears to be relatively non-toxic.
In B. fragilis endocarditis, metronidazole, because of its rapidly bactericidal action, may become the drug of choice and should probably be included in the antimicrobial regimen.
Prospective studies in patients undergoing elective colonic surgery have demonstrated that administration of metronidazole before, and for up to 7 days after surgery, in conjunction with other antimicrobial agents, significantly reduces the frequency of postoperative infection and eliminates non-sporing anaerobic infection. Wound infections caused by facultative organisms occurred in some patients treated with metronidazole, but generally less frequently than in those not so treated.
Administration of metronidazole 1 to 2g on admission and 200mg thrice daily for up to 7 days after surgery decreased the frequency of infections and virtually eliminated anaerobic infection after emergency appendicectomy or elective hysterectomy.
The indications for prophylactic antibiotics in elective bowel surgery are still debated, but results of studies using metronidazole in addition to kanamycin, neomycin or phthalylsulphathiazole provide strong evidence that anaerobic bacteria (particularly Bacteroides sp.) are the major contributors to intra-abdominal and wound infection after colon surgery.
Side Effects: Side effects have seldom been reported in patients treated with metronidazole for anaerobic infection. The use of higher than usual dosages has resulted in occasional instances of parasthesiae of the feet and hands, peripheral neuropathy and epileptiform seizures. Further studies are needed to determine the frequency and nature of adverse effects likely to be encountered with the higher dosages and greater duration of metronidazole treatment sometimes necessary for the treatment of severe anaerobic infections.
Dosage: In the treatment of anaerobic infections, the usual adult oral dosage is 400mg* 3 times daily for 7 days or longer according to the clinical response. The oral dosage in infants and children is 7.5mg/kg 3 times daily. If rectal suppositories are to be used, adults should receive 1g 3 times daily for 3 days and then 12-hourly for 4 days, the corresponding children’s (5 to 12 years) dose being 0.5g administered as for adults. Younger children should receive 250mg doses for 1 to 5 year olds and 125mg doses for those under 1 year. Oral medication should be resumed as soon as possible.
By intravenous infusion, the usual dosage for adults is 500mg in 100ml solution 8-hourly,† administered at a rate of 5ml per minute. For children under 12 years the intravenous dosage is 7.5mg/kg infused as for adults.
In the prevention of anaerobic infection in gynaecological surgery, 1g orally as a single dose followed when possible by 200mg orally, 3 times daily for up to 7 days after surgery is the recommended regimen. In elective colonic surgery, metronidazole has been successfully used when given alone (1 g orally as single dose, 200mg 8 hourly thereafter when possible and 1 g rectally 8 hourly during periods when oral medication is not possible, for a total of 7 days treatment) and when given concomitantly with kanamycin or phthalylsulphathiazole (see section 10.2).
Unable to display preview. Download preview PDF.
- Amon, I.; Amon, K. and Huiler, H.: Pharmacokinetics and therapeutic efficacy of metronidazole at different dosages. International Journal of Clinical Pharmacology 16: 384 (1978).Google Scholar
- Bannatyne, R.-M. and Harnett, N.M.: Metronidazole and acne. Acta dermato-venereologica (Stockholm) 56: 307–308 (1976).Google Scholar
- Baron, D.; Drugeon, H.; Nicolas, F. and Courtieu, A.L.: Les infections severes a Bacteroides fragilis: Traitement par le metronidazole. Donnees cliniques et pharmacologiques. Medecine et Maladies Infectieuses 7(3): 158 (1977).Google Scholar
- Bartlett, J.G.: Head and neck, bone and joint, and chest infections, bacteraemia and endocarditis due to non-sporeforming anaerobes; in Phillips and Sussman (Eds) Infection with Non-sporing Anaerobic Bacteria, p.131 (Churchill Livingstone, 1974).Google Scholar
- Bartlett, J.G.; Gorbach, S.L.; Tally, F.P. and Finegold, S.M.: Bacteriology and treatment of lung abscess. American Review of Respiratory Diseases 109: 510 (1974b).Google Scholar
- Beard, C.M.; Nolier, K.L.; O’Fallon, W.M. and Kurland, L.T.: Is metronidazole (‘Flagyl’) carcinogenic in humans. Paper presented at the Preventative Oncology Meeting, Washington, D.C. March 1978.Google Scholar
- Bittner, J. and Ardeleanu, J.: Preventative action of metronidazole on experimental C. perfringens induced gas gangrene in guinea pigs; in Finegold (Ed) Metronidazole. Proceedings of the International Metronidazole Conference, Montreal, May 1976, p.329 (Excerpta Medica, 1977).Google Scholar
- Bittner, J. and Munteanu, V.: Potentiating action of combining metronidazole and penicillin against C. perfringens in vitro; in Finegold (Ed) Metronidazole. Proceedings of the International Metronidazole Conference, Montreal, May 1976, p.293 (Excerpta Medica, 1977).Google Scholar
- Bost, R.G.: Metronidazole: Toxicology and teratology; in Finegold (Ed) Metronidazole. Proceedings of the International Metronidazole Conference, Montreal, May 1976, p.112 (Excerpta Medica, 1977a).Google Scholar
- Bost, R.G.: Metronidazole: Mammalian mutagenicity; in Finegold (Ed) Metronidazole. Proceedings of the International Metronidazole Conference, Montreal, May 1976, p.126 (Excerpta Medica, 1977b).Google Scholar
- Bradnum, P. and Hood, F.J.C.: Metronidazole in the treatment of severe acute pericoronitis. Brit. Dent. J. 142: 313 (1977).Google Scholar
- Cella, P.L.: Experimental studies on the teratology on metronidazole. Rivista di Patologia e Clinica 24(9): 529 (1969).Google Scholar
- Cerat, G.A.; Cerat, L.L.; McHenry, M.C.; Wagner, J.G.; Hall, P.M. and Gavan, T.L.: Metronidazole in renal failure; in Finegold (Ed) Metronidazole. Proceedings of the International Metronidazole Conference, Montreal, May 1976, p.404 (Excerpta Medica, 1977).Google Scholar
- Chow, A.W.; Bendnorz, D. and Guze, L.B.: Susceptibility of obligate anaerobes to metronidazole: An extended study of 1,054 clinical isolates; in Finegold (Ed) Metronidazole. Proceedings of the International Metronidazole Conference, Montreal, May 1976, p.286 (Excerpta Medica, 1977).Google Scholar
- Corrodi, P.; Busch, D.F.; Sutter, V.L.; Wideman, P.A.; Citronbaum, D.M. and Finegold, S.M.: Factors affecting the in vitro antibacterial activity of metronidazole; in Finegold (Ed) Metronidazole. Proceedings of the International Metronidazole Conference, Montreal, May 1976, p.299 (Excerpta Medica, 1977).Google Scholar
- De Carneri, I.; Cantone, A.; Emanueli, A.; Giraldi, P.N.; Logemann, W.; Meinardi, G.; Monti, G.; Nannini, G.; Tosolini, G. and Vita, G.: Nitrimidazine: a new trichonomacide. Paper presented at 6th International Congress of Chemotherapy, Tokyo, August 1969.Google Scholar
- Douglas-Smith, B.J. and Wellingham, J.: Metronidazole in treatment of empyema. Brit. med. J. 1: 1074–1075 (1976).Google Scholar
- Dublanchet, A.; Durieux, R. and Fevre, D.: Sensibilite des bacteries anaerobies au metronidazole. Medicine et Maladies Infectieuses 7: 317 (1977).Google Scholar
- Edwards, D.I.; Knight, R.C. and Kantor, I.: Interaction of nitroimidazole drugs with DNA; in Siegenthaler and Luthy (Eds) Current Chemotherapy, Proceedings of the 1 Oth International Congress of Chemotherapy, Vol. 2, p.714–716 (American Society for Microbiology, Washington DC, 1978).Google Scholar
- Eykyn, S. and Phillips, I.: Intravenous metronidazole in the treatment of anaerobic sepsis; in Finegold (Ed) Metronidazole, p.393 (Excerpta Medica, 1977).Google Scholar
- Feiner, J.M. and Dowell, V.R.: Anaerobic bacterial endocarditis. New England Journal of Medicine 283: 1188 (1970).Google Scholar
- Ferguson, I.R.: The assay of metronidazole; in Finegold (Ed) Metronidazole. Proceedings of the International Metronidazole Conference, Montreal, May 1976, p.23 (Excerpta Medica, 1977).Google Scholar
- Finegold, S.M.: Intra-abdominal, genitourinary, skin and soft tissue infections due to non-sporeforming anaerobic bacteria; in Phillips and Sussman (Eds) Infection with Non-sporing Anaerobic Bacteria p.160 (Churchill Livingstone, 1974).Google Scholar
- Finegold, S.M. and Sutter, V.L.: Antimicrobial susceptibility of anaerobic Gram-negative bacilli; in McPhee (Ed) Host Resistance to Commensal Bacteria, p.275 (Churchill Livingstone, 1972).Google Scholar
- Fuzi, M. and Csukas, Z.: Das antibakterielle wirkungs spektrum des metronidazols. Infektions krankheiten und Hygiene. I. Abt Medizinisch-Hygienische virus forschung und Parasitologie Originale 213: 258 (1970).Google Scholar
- Garcia Rodriguez, J.A.; Garcia Sanchez, J.E.; Saenz Gonzalez, M.C. and Prieto Prieto, J.: The sensitivity of anaerobic Gram-negative bacilli to four nitroimidazole derivatives. Phar-matherapeutica 1: 573 (1977).Google Scholar
- Gillespie, G. and McNaught, W.: Prophylactic oral metronidazole in intestinal surgery; in Finegold (Ed) Metronidazole, p.385 (1977).Google Scholar
- Houghton, G.W.; Smith, J. and Thorne, P.S.: Comparison of the pharmacokinetics of metronidazole and its metabolites 14041 RP and 20396 RP in healthy female volunteers following either a single oral or intravenous dose (500mg) of ‘Flagyl’. Unpublished data, May and Baker, 1978.Google Scholar
- Hunt, W.L.; Agre, K.; Opperman, J. and Nissen, C.H.: Flagyl (metronidazole) in the treatment of anaerobic infections. Abstract of Paper presented at Meeting of American Society of Microbiology, May 1978.Google Scholar
- Hutchinson, M.; Lambert, H.P.; Loughman, D. and Morgan, M.W.E.: Metronidazole in experimental peritonitis; in Finegold (Ed) Metronidazole. Proceedings of the International Metronidazole Conference, Montreal, May 1976, p.320 (Excerpta Medica, 1977).Google Scholar
- Ings, R.M.J.; McFadzean, J.A. and Ormerod, W.E.: The mode of action of metronidazole in Trichomonas vaginalis and other micro-organisms. Biochem. Pharmacol. 23: 1421 (1974).Google Scholar
- Jones, P.H.; Willis, A.T. and Ferguson, I.R.: Treatment of anaerobically infected pressure sores with topical metronidazole. Lancet 1: 214 (1978).Google Scholar
- Jorgenson, T.A. and Rushbrook, C.J.: Heritable translocation study of metronidazole. Stanford Research Institute. Unpublished data (1977).Google Scholar
- Krazmier, F.J.: A significant interaction between metronidazole and warfarin. Mayo Clinic Proceedings 51: 782 (1976).Google Scholar
- La Russo, N.F.; Lindmark, D.G. and Muller, M.: Hepatic metabolism and biliary excretion of metronidazole. Gastroenterology 70(5) Abstract A47/905 (1976).Google Scholar
- La Russo, N.F.; Tomasz, M.; Kaplan, D. and Muller, M.: Absence of strand breaks in deoxyribonucleic acid treated with metronidazole. Antimicrobial Agents and Chemotherapy 13: 19 (1978).Google Scholar
- La Russo, N.F.; Tomasz, M.; Muller, M. and Lipman, R.: Interaction of metronidazole with nucleic acid in vitro. Molecular Pharmacology 13: 872 (1977).Google Scholar
- Laufer, J.; Mignon, H. and Videau, D.: L’association metronidazole-spiramycine: Concentrations et synergie in situ comparees aux CMI de la flore buccale. Revue de Stomatologie 74: 387 (1973)Google Scholar
- Ledger, W.J.; Gee, C.L.; Pollin, P.A.; Lewis, W.P.; Sutter, V.L. and Finegold, S.M.: A new approach to patients with suspected anaerobic postpartum pelvic infections. Transabdominal uterine aspiration for culture and metronidazole for treatment Am. J. Obstet. Gynae. 126: 1 (1976).Google Scholar
- Ledger, W.J.; Lewis, W.; Golde, S. and Gee, C.: The use of metronidazole in obstetric and gynecologic infections; in Finegold (Ed) Metronidazole, Proceedings of the International Metronidazole Conference, Montreal, May 1976, p.353 (Excerpta Medica, 1977).Google Scholar
- Lefebvre, Y. and Hesseltine, H.C.: The peripheral white blood cells and metronidazole. Journal of the American Medical Association 191: 15 (1965).Google Scholar
- Long, S.; Mueller, S. and Swenson, R.M.: Antibiotic susceptibilities of subspecies of Bacteroides fragilis. Paper presented at the 15th Interscience Conference of Antimicrobial Agents and Chemotherapy, Washington Sept 1975.Google Scholar
- McGilveray, I.J.; Midha, K.K.; Loo, J.C.K. and Cooper, J.K.: The bioavailability of commercial metronidazole formulations. International Journal of Clinical Pharmacology 16: 110 (1978).Google Scholar
- Mee, W.M.: Metronidazole prophylaxis and primary wound closure in appendicectomy; in Willis, Leigh and Hamilton-Miller (Eds), Symposium on Management of Non-clostridial Anaerobic Infections. Journal of Antimicrobial Chemotherapy (Suppl. C) (In press, 1978).Google Scholar
- Mitchell, A.D.: Unscheduled DNA synthesis testing of metronidazole. Stanford Research Institute, Unpublished data (1976).Google Scholar
- Monro, A.M.: Blood levels of chemotherapeutic drugs and the pharmacokinetics of tinidazole and metronidazole. Current Therapeutic Research and Opinion 2: 130 (1974).Google Scholar
- Muller, M. and Lindmark, D.G.: Effect of oxygen on the uptake of metronidazole by trichomonads and Clostridium pasteurianum. Abstract of Paper Presented at the 15th Inter-science Conference on Antimicrobial Agents and Chemotherapy, Washington, Sept, 1975.Google Scholar
- Muller, M.; Lindmark, D.G. and McLaughlin, J.: Mode of action of metronidazole on anaerobic microorganisms; in Finegold (Ed) Metronidazole, Proceedings of the International Metronidazole Conference, Montreal, May 1976, p.12 (Excerpta Medica, 1977).Google Scholar
- O’Brien, R.W. and Morris, J.G.: Effect of metronidazole on hydrogen production by Clostridium acetobutylicum.Arch. Mikrobiol. 81: 225 (1972).Google Scholar
- Oderdonk, A.B.; Hermos, J.A.; Dzink, J.L. and Bartlett, J.G.: Protective effect of metronidazole in experimental ulcerative colitis. Gastroenterology 74: 521 (1978).Google Scholar
- O’Grady, L.R. and Ralph, E.D.: Anaerobic meningitis and bacteremia caused by Fusobacterium species. American Journal of Diseases of Childhood 130: 871 (1976).Google Scholar
- Oppermann, J.; Azarnoff, D.; Hunt, W.; Shierk, D.; Muir, R. and Ranney, R.: Pharmacokinetics of intravenously administered 14C-metronidazole hydrochloride in man. Abstract of paper presented at meeting of American Society of Microbiology, May, 1978.Google Scholar
- Pieron, R.; Meyniel, D.; Mafart, Y.; Bryskier, A. and Vergez, P.: Un cas de septicemie a clostridium subterminale avec localisations articulaires. Traitement par le metronidazole. Medicine et Maladies Infectieuses 7: 270 (1977b).Google Scholar
- Plant, C.W. and Edwards, D.I.: The effect of tinidazole, metronidazole and nitrofurazone on nucleic acid synthesis in Clostridium bifermentans. Journal of Antimicrobials and Chemotherapy 2: 203 (1976).Google Scholar
- Ralph, E.D. and Kirby, W.M.M.: Unique bactericidal action of metronidazole against B. fragilis and C. perfringens. 15th Intersci. Conf. Antimicrob. Ag. Chemother., 24–26th September, 1975a, Washington, DC.Abstr. 382.Google Scholar
- Ralph, E.D. and Kirby, W.M.M.: Human pharmacology of oral metronidazole as determined by bioassay; in Finegold (Ed) Metronidazole. Proceedings of the International Metronidazole Conference, Montreal, May 1976, p.50 (Excerpta Medica, 1977).Google Scholar
- Roe, F.J.C.: Metronidazole: Tumorigenicity studies in mice, rats and hamsters; in Finegold (Ed) Metronidazole. Proceedings of the International Metronidazole Conference, Montreal, May 1976, p.132 (Excerpta Medica, 1977a).Google Scholar
- Rosenkranz, H.S. and Speck, W.T.: Studies on the significance of the mutagenicity of metronidazole for Salmonella typhimurium; in Finegold (Ed) Metronidazole. Proceedings of the International Metronidazole Conference, Montreal, May 1976, p.119 (Excerpta Medica, 1977).Google Scholar
- Rust, J.H.: An assessment of metronidazole tumorigenicity: Studies in the mouse and rat; in Finegold (Ed) Metronidazole. Proceedings of the International Metronidazole Conference, Montreal, May 1976, p.138 (Excerpta Medica, 1977).Google Scholar
- Schwartz, D.E. and Jeunet, F.: Comparative pharmacokinetic studies of ornidazole and metronidazole in man. Chemotherapy (Basel) 22: 19 (1976).Google Scholar
- Selkon, J.B.; Hale, J.H. and Ingham, H.R.: Metronidazole in the treatment of anaerobic infection in man, in Williams and Geddes (Eds) Chemotherapy. Proceedings of the 9th International Congress of Chemotherapy, London 1975, p.277 (Plenum Press, 1976).Google Scholar
- Semb, L.S.; Dyrstad, A.; Johnsrud, M-L.; Grabner, P.J. and Viddal, K.O.: A double blind study of metronidazole in preoperative treatment before colorectal surgery. Scandinavian Journal of Gastroenterology 12(Suppl. 45): 94 (1977).Google Scholar
- Shinn, D.L.: Vincent’s Disease and its Treatment; in Finegold (Ed) Metronidazole. Proceedings of the International Conference on Metronidazole, Montreal, May 1976, p.334 (Excerpta Medica, 1977).Google Scholar
- Sonnenwirth, A.C.: Incidence of intestinal anaerobes in blood cultures; in Balows, De Haan, Dowell and Guze (Eds) Anaerobic Bacteria: Role in disease, p.157 (Charles C. Thomas, Illinois, 1974).Google Scholar
- Stratford, B.C. and Dixson, S.: Intestinal asepsis with metronidazole, framycetin, and ampicillin. A preliminary report on 20 patients; in Siegenthaler and Luthy (Eds) Current Chemotherapy, Proceedings of the 10th International Congress of Chemotherapy, Vol. 2, p.270–272 (American Society for Microbiology, Washington 1978).Google Scholar
- Study Group: An evaluation of metronidazole in the prophylaxis and treatment of anaerobic infections in surgical patients. Journal of Antimicrobial Chemotherapy 1(4): 393 (1975).Google Scholar
- Sutter, V.L. and Finegold, S.M.: In vitro studies with metronidazole against anaerobic bacteria; In Finegold (Ed) Metronidazole. Proceedings of the International Metronidazole Conference, Montreal, May 1976, p.279 (Excerpta Medica 1977).Google Scholar
- Tabaqchali, S.: Ecology and metabolic activity of non-sporing anaerobes; in Phillips and Sussman (Eds) Infection with Non-sporing Bacteria, p. 59 (Churchill Livingstone, 1974).Google Scholar
- Ueno, K.; Ninomiya, K. and Suzuki, S.: Antibacterial activity of metronidazole against anaerobic bacteria. Chemotherapy (Tokyo) 19: 111 (1971).Google Scholar
- Ueno, K.: Antibacterial action of metronidazole (‘Flagyl’) against anaerobes in vivo. Unpublished data.Google Scholar
- Warner, J.F. and Prior, R.B.: Clinical and in vitro studies of the bactericidal activity of metronidazole against anaerobic bacteria, in Finegold (Ed) Metronidazole. Proceedings of the International Metronidazole Conference, Montreal, May 1976, p.359 (Excerpta Medica, 1977).Google Scholar
- Watt, B. and Jack, E.P.: What are anaerobic cocci? Journal of Medical Microbiology 10: 462 (1977).Google Scholar
- Watt, B. and Jack, E.P.: Susceptibility of anaerobic cocci to imidazole derivatives with special reference to metronidazole and sulnidazole; in Siegenthaler and Luthy Current Chemotherapy, Proceedings of the 10th International Congress of Chemotherapy, Zurich, Sept. 1977, Vol. 2, p.716 (American Society for Microbiology, Washington 1978).Google Scholar
- Weinstein, L. and Rubin, R.H.: Infective endocarditis. Progress in Cardiovascular Disease 16: 239 (1973).Google Scholar
- Welling, P.G. and Monro, A.M.: The pharmacokinetics of metronidazole and tinidazole in man. Arzneimittel Forschung 22: 2129 (1972).Google Scholar
- Willis, A.T.; Ferguson, I.R.; Jones, P.H.; Phillips, K.D.; Tearle, P.V.; Berry, R.B.; Fiddian, R.V.; Graham, D.F.; Harland, D.H.C.; Innes, D.B.; Mee, W.M.; Rothwell-Jackson, R.L.; Sutch, I.; Kilbey, C. and Edwards, D.: Metronidazole in prevention and treatment of Bacteroides infections after appendicectomy. British Medical Journal 1: 318 (1976).PubMedGoogle Scholar
- Willis, A.T.; Ferguson, I.R.; Jones, P.H.; Phillips, K.D.; Tearle, P.V.; Fiddian, R.V.; Graham, D.F.; Harland, D.H.C.; Hughes, D.F.R.; Knight, D.; Mee, W.M.; Pashby, N.; Rothwell-Jackson, R.L.: Sachdeva, H.K.; Sutch, I.; Kilbey, C. and Edwards, D.: Metronidazole in prevention and treatment of bacteroides infections in elective colonic surgery. British Medical Journal 1: 607 (1977).PubMedGoogle Scholar
- Wise, R. and Bedford, K.: The activity of eight antimicrobial agents, including three nitroimidazole compounds against 40 clinical isolates of Bacteroides spp. 9th International Congress of Chemotherapy, London (1975).Google Scholar