Metronidazole

Symposium on Antimicrobial Therapy

Metronidazole Ahdolghader Molavi, MD.,* Jack L. LeFrock, MD.,t and Randall A. Prince, Pharm D.f

Metronidazole was discovercd in France in 1957 and became the drug of choice for treatment of trichomoniasis. It was subsequently proven to be effective for both amebiasis and giardiasis. Although its activity against anaerobic bacteria was first noted in 1962, the clinical implicatiolls were not fully appreciated fc)r more than a decade. Subsequent clinical trials demonstrated its efficacy for treatment of infections caused by anaerobic bacteria, including Bacteroides fragilis. Metronidazole is a nitroimidazole drug: 1-(beta-hydroxyethyl)-2-methyl-.5-nitroimidazole. It is highly active against obligate anaerobes but does not have clinically significant activity against facultative an aerobes and obligate aerobes.

MODE OF ACTION Metronidazole is a compound of low molecular weight (molecular weight, 171), which diffuses equally well into aerobic and anaerobic bacteria. 90, 1:\. The common characteristic of the sensitive organisms is that they are anaerobic and contain lowredox-potential electron-transport proteins (ferridoxin-like and flavodoxin-like). These proteins are capable of reducing the nitro group of metronidazole by a nonenzymatic chemical reaction. 29 ,H2,94 Reduction plays a dual role:",,91 It decreases the intracellular concentration of the unchanged drug and thus maintains a gradient driving the uptake, and it generates compounds that are toxic to the cell. The toxicity is mediated not by the final products of reduction, but by unstable intermediate compounds or free radicals. K9 The available evidence indicates that the toxic transitory products bind to DNA and inhibit its synthesis, resulting in cell death. 17,28,30,63,76 Inhibition of growth and protein synthesis by chloramphenicol has no effect on the bactericidal activity of metronidazole against B. fragilis .11'

*Associate Professor of Medicine, Division of IlIfectious Diseases and Clinical ~Hcrohiology, Hahnemann Medical College and Hospital, Philadelphia, Pennsylvania tProf(~ssor of f\'1cdicine and Chief, Divisioll of Infections Dis('ascs alId (~lil1ical !\-iicrobioiogv, Hahncmallll ' Medical College and Hospital, Philadelphia, Pennsylvania ;Associate Professor of (:linical Phanlltlcy, University of Iowa C()llege of Phannacy, Iowa City, Iowa

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ANTIMICROBIAL SPECTRUM Gram-Negative Anaerobic Bacilli Metronidazole is active in vitro against gram-negative anaerobic bacilli, especially B. fragilis .S3 Ninety-five per cent of strains of B. fragilis are inhibited by 8 fLg per ml or less. lH.I33 Bacteroides melaninogenicus is also quite sensitive; nearly all strains are inhibited by 2.0 fLg per ml or less. IH.ll3 Other Bacteroides spp., with the exception of B. pneumosintes and B. corrodens, are equally susceptible. IH Of the latter two species, only half the strains are inhibited by 6.25 J,Lg per ml. Fusobacterium spp., including F. nucleatum, are highly sensitive to metronidazole. Nearly all strains are inhibited by 1.0 fLg per ml or less.IH.I33 Metronidazole is bactericidal against obligate anaerobes. The minimal bactericidal concentrations (MBC) are the same or one dilution higher than the minimal inhibitory concentrations (MIC). 20.92.132.11.0.146 The bactericidal effect of metronidazole is rapid, 101.106.1.14 and the killing rate is proportional to the concentration of the drug. 22 Comparison of the bactericidal activity of penicillin G, carbenicillin, clindamycin, and metronidazole against strains of B . fragilis and Clostridium perfringens showed that metronidazole had the most rapid killing rate, while clindamycin had the slowest. 106 The susceptibility of anaerobic bacteria to metronidazole is affected only slightly by the inoculum size.69.1OI.134 Changes of pH within the range from .5.5 to 8.0 do not significantly affect its activity.!OI There is no antagonism between metronidazole and various other antibiotics, including clindamycin, rifampin, and ticarcillin, against B. fragilis strains. lO2

Gram-Positive Anaerobic Bacilli Metronidazole is highly active against Clostridia, including C. perfringens, C. novyi, C. sporogenes, and C. hifermentans. Nearly all strains are inhibited by 2.0 fLg per ml or less. lH.25.8.3.1.33 Some strains of C . ramosum require higher concentrations for inhibition. 135 Mctronidazole is relatively ineffective against anacrobic, nonsporeforming, gram-positive bacilli. Propionibacterium spp., including P. acne and P. granulosum, are mostly resistant. 7 . 18 Only half of the strains of Eubacterium, Bifidobacterium, and Lactobacillus are inhibited by 8.0 fLg per ml or less.IS.lll :\lost strains of Actinomyces are resistant. sO.l.3.'

Anaerobic Cocci Metronidazole is active against anaerobic gram-negative and gram-positive cocci. Most strains of Peptococcus and PeptostreptococclIs arc inhibited by 6.25 fLg per ml or less. lb. 13.1 Veillonella spp. are also sensitive; two-thirds of the strains are inhibited by 6.25 fLg per ml or less. lH

Other Bacteria and Protozoa Under conditions of extreme anaerobiosis, metronidazole is active against some facultatively anaerobic organisms, including Escherichia coli, Klehsiella, and Proteus. 60 Nearly half of the strains of Gardnerella wginalis (H emophilus vagina/is) are inhihited hy 8 J,Lg per ml under anaerohic conditiolls. ,03 \lost strains of Campylobacter fetus are sensitive. l\J

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,\ietronidazolc is active against anaerobic protozoa, including Trichomonas vagina/is, Entamoeba izisto/Utica, Giardia lam/,/ia, and Balantidium coli.

THERAPEUTIC AND PROPHYLACTIC USES Anaerobic Infections ,\ietronidazole is an alternative to c1indalllyein f()r the treatment of serious amlCrohic infections, particularly those caused by B. jragilis. For thcse infections, the drug is usually administered intravenously. The officially approved adult dosage is 15 Illg per kg (1 gm for a 70 kg adult) as a loading dose followed by maintenance doses of 7.5 Illg per kg (500 mg for a 70 kg adult) every six hours. Each dose is diluted to less than 8 mg per ml, neutralized with sodium bicarbonate (1 mEq for each 100 mg), and infused slowly over one hour. Neutralized solutions should not be refrigerated, lest precipitation occurs. Parcnteral therapy can he changed to oral administration, at the same dosage, when conditions warrant. Metronidazole is an effective drug f()r the treatment of anaerobie infections of various types. Many of these infections are mixed in that both aerohic and anaerobic organisms are implicated, so that it is often necessary to comhine metronidazole with a suitable antimicrobial agent active against aerobic bacteria. ,\iost of these infections also require appropriate surgical intervention. Metronidazole, comhined with another antimicrobial agent active against gramnegative aerobes, has been effective {(H' the treatment of intraabdominal infections. 3I ,3-,,16,145.147 In a prospective, double-hlind study metronidazole (500 mg every eight hours) was as effective as c1indamycin (600 mg every eight hours), each combined with tobramycin and administered intravenously for treatment of intraabdominal sepsis. 127 Pelvic infections following childhirth or gynecologic surgery have been successfully treated with metronidazole, often combined with a suitable agent active against aerobes ..34,lh,77.J:lO,I:ll Anaerobic pleuropulmonary infections have been successfully treated with metronidazole. 26 ,32,-16,13h Treatment failures have occurred when aerobic bacteria were also present and metronidazole was used alonc. 12o The drug has becn dfective for bactcrcmia and endocarditis caused by anaerohic, gram-negative hacilli (particularly F. necrophorum and B . jragilis) , including strains resistant to c1indamycin and chloramphenicol. 43,02,67,12:1,121. l:Jh ,\ietronidazole, either alone or in combination with other antibiotics, has been used successfully to trcat brain abscess .•",(;2,63,111 Bacteroides jragilis meningitis, including cases that failed to respond to chloramphenicol, has been curcd with metronidazole. '2 ,16,:17 The drug is effective f()r ostcomyelitis and septic arthritis caused by anaerobic bacteria, l2,l.16,14.', 152 In conjunction with surgery, it has been used successfidly to managc gas gangrcne. 35 •46

Administered orally, metronidazole is effective f()r acute dental infections, i. e" pericoronitis and apical infection,6LH3 and Vinccnt's gingivostomatitis. 12., It has produced rapid clinical rcsponsc in patients with antibiotic-induced colitis. ".b4,'" 1,10 Metronidazolc is rapidly bactericidal against susceptible bacteria, it penetrates well into the brain j ,,61 and the cerebrospinal fluid, 6H,"', J(H 111 and it is not susceptible to the beta-lactamases produced by many an
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system infections, including meningitis and brain abscess, especially those caused by B .fragilis; B .fragilis endocarditis; and infections eau sed by c1indamycin-rcsistant and/or chloramphcnicol-rcsistant strains of B. fragilis.

Nonspecific Vaginitis The cause of nonspccific vaginitis is in dispute. Thc predominant vaginal flora in this syndrome consists of G. vaginalis (Hemophilus vaginalis) and anaerobes, including Bacteroides spp. (other than B, fragilis) and Peptococcus spp. 12' The relative roles of anaerobes and G. vagina lis , as well as their pathogenetic mechanisms, are still unknown. Metronidazole, administered orally at a dose of 500 mg twice daily for seven days, is 94 to 100 per cent effeetive for this condition. 6 . fJ8

Trichomoniasis Metronidazole, administered orally, is highly effective for trichomonal vaginitis. Systemic therapy eradicates trichomonads from the urinary tract as well as from the vagina. Various dosage schedules appear to be equally effective. These include 250 mg three times daily for seven days, 500 mg twice daily for five days,44 and a single dose of 2.0 grams. 23 ,27,,'54.112.139.].50 Inadequate compliance is the major cause of treatment failure. When noncompliance is suspected, single-dose treatment is prcferable. Initial simultaneous treatment of male conjugal partners remains controversial. In most cases the male partner harbors trichomonads in his urine, even though he has no symptoms of infection. For women with recurrent infection, concurrent treatment of the male partner is recommended.

Amebiasis Metronidazole has a rapid amebicidal cffect in vivo!8 and is the drug of choice for amebiasis. 2,3,13 For intestinal infection (symptomatic or asymptomatic), liver abscess, or other forms of extraintestinal amebiasis, an oral dose of 750 mg three times daily (in children, 35 to 50 mg per kg daily in three divided doses) for five to ten days is recommended. This regimen gives a cure rate of 92 per cent in amebic dysentery and nearly 100 per cent in amebic liver abscess. 1 If oral treatment is not feasible, the drug can be administered intravenously. Because cysts may persist in stool after successful treatment of amebic liver abscess or dysentery, the use of an intraluminal amebicide after treatment with metronidazole has bcen recommended. 2 Amebic liver abscess has sometimes failed to respond to metronidazole.3H·51.71,loo These cases should be treated with emetine, chloroquine, and an intraluminal amebicide.

Giardiasis Metronidazole, administered orally, is effective for giardiasis. Various dosage schedules appear to be effective. These include 250 mg three times daily for seven days and two grams once a day for three days. ].,1 Giardiasis is not an approved indication for metronidazole in the United States. Quinacrine is commonly used to treat this infection. In a prospective study of giardiasis in infants and children, metronidazole was more effective than quinacrine in eradicating the parasite. 70

Prophylactic Uses Several controlled trials have indicated that metronidazole provides effective prophylaxis in surgical operations with a high risk of postoperative anaerobic infec-

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tion. Perioperative administration of metronidazole significantly reduces the incidence of infection after both vaginal and abdominal hysterectomy and caesarean section.·'·59,!;7.]30.131 In this regard metronidazole is as effective as a cephalosporin. '5.142 Prospective studies of patients undergoing elective colonic surgery have demonstrated that perioperative administration of metronidazole, either alone or in conjunction with an aminoglyeoside, significantly reduccs the incidence of postoperative wound and intraabdominal anaerobic infections. I 1,24 ..33.36,47,53, 1.17148 The combination of metronidazole and an aminoglycoside appcars to be superior to metronidazole alone for this purpose. 141 Prophylactic metronidazole, administered preoperatively or perioperatively, reduces significantly the incidence of wound infection after appendectomy, especially when the appendix is gangrenous or perfi)rated. 40,50,99. J08,IHJ. 147

PHARMACOKINETICS Absorption Metronidazole administered orally is almost completely absorbed from the intestinal tract. The absorption rate varies in different individuals. Peak serum concentrations are attained at varying times (usually one to threc hours) after an oral dose. A single dose of 250 mg administered orally to adults produces mean peak serum concentrations of 5.1 to 6.2 fLg per mI.4.81.J04 Following a 500 mg dose, the peak levels average 11.5 to 13 fLg per ml. 57 ,J(M The serum concentrations decline slowly, averaging 0.65 and 1.36 fLg per ml, 25 hours after a 250 mg or 500 mg dose, respectively. Single dose pharmacokinetics are not dose-dependent. 149 The peak serum level varies almost linearly with the dose: 19,6 fLg per ml after an oral dose of 1 gm and 40 to 41 fLg per ml after 2 gm,'U49 The serum half-life has varied in different studies from 7,0 to 8,7 hours. 57 ,104,122 Absorption of metronidazole is not significantly decreased by concomitant food ingestion, Peak serum concentrations are the same whether the drug is given on an empty stomach or after food; however, there may be a marked effect on time to reach peak concentration. 86 A single 500 mg dose infused intravenously to adults over 20 minutes produces a mean peak serum concentration of 18 fLg per ml at the end of the infusion.57 Following an initial rapid decline, which is due to distribution from blood into tissues, the serum concentration falls gradually, with a mean half-life of 7.3 hours. With a repeated dosage regimen, the serum levels increase progressively and reach a steady state after a fcw doses. With a 500 mg dose infused intravenously (over 20 minutes) every eight hours, the peak and trough serum concentrations at the steady state average 26 and 12 fLg per m!, respectivcly.57 When a loading dose of 15 mg per kg is infused intravenously and followed by maintenance doses of 7.5 mg per kg every six hours (all infusions given over one hour), the peak steady-state scrum levels average 25.9 fLg per ml, with troughs averaging 18.3 fLg per ml. 3\) These concentrations are attained after the second dose. Without a loading dose, the steady-state levels do not occur until at least the second day of therapy. Metronidazole is absorbed slowly when given rectally via a suppository. A suppository dose of 500 mg produces a mean peak serum concentration of 5.1 fLg per ml at four to 12 hours."" With a 1 gm suppository dose, thc peak serum concentration

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is achieved at seven to 15 hours and averages 7.3 J.Lg per m!. Systcmic availahility of metronidazole from the suppository formulation is 82 and 67 per cent for doses of 500 mg and 1 gm, respectively." Variations in the values reported for the pharmacokinetic parameters are in part due to interstudy assay differences. The hioassay filr metronidazole is appropriate for therapeutic interpretations; however, phannaeokinetie analyses require the utilization of more specific assays such as high-pressure liquid chromatography ..'2

Distribution Metronidazole at a eoncentration of 8 J.Lg per ml is 1 per cent hound to plasma proteins, as determined hy ultrafiltration. J04 Other techniques have given values of less than 4 per cent, l2l 11.2 per cent, l22 or 20 per cent." The ahsence of significant protein binding and the small size of the molecule favor good distribution throughout hody tissues and fluids. The drug has, therefore, a large apparent volume of distrihution, equivalent to 70 to 94.4 per cent (mean, 83 per cent) of body weight. l22 Metronidazole penetrates well into vaginal seeretions, seminal fluid, saliva, and breast milk. 49 Therapeutically adequate concentrations are attained in empyema fluid '26 and hepatic abscesses. I.3H The drug readily penetrates into p~lvic tissues, and the concentrations attained in the myometrium and Fallopian tubes are nearly the same as the concomitant serum levels.:ll The concentrations in the alveolar bone approximate those in serum. III Metronidazole penetrates well into the cerebrospinal fluid. With normal meninges, the spinal fluid levels are approximately half of the simultaneous serum concentrations.69.l44 In patients with meningitis, the cerebrospinal fluid concentrations approximate those in serum. 9.5. lO-l The drug readily penetrates into hrain abseesses where it attains eoneentrations equal to those in serum. 4",64 In patients with normal biliary tract, metronidazole enters the hile in coneentrations similar to those in serum and is eoncentrated in the gallbladder. 9.3 In patients with gallstones and a nonfunctioning gallbladder, the gallhladder hile eoncentrations are significantly lower than those in scrum. >13

Excretion Only 15 per cent of an orally administered dose of metronidazole is excreted unchanged in the urine. j()4 The urinary coneentrations during the first 12 hours average 88 and 35 J.Lg per ml for doses of 500 mg and 250 mg, respectively. Most of the administered metronidazole is metabolized in the liver. The metabolites, whieh are excreted in the urine, include a number of oxidative products and glucoronic acid conjugates. 66, l29 Approximately 25 per cent of the administered dose appears in the urine as a hydroxy metabolite, 1-(beta-hydroxymethyl)-2-hydroxymethyl-5-nitroimidazole, and 14 per cent as conjugates of metronidazole and its hydroxy metabolite. Some of the oxidative metabolites have antibacterial activity; the hydroxy metabolite possesses 30 per cent of the activity of the parent compound against Clostridium spp. \06 Approximately 14 per cent of an orally administered dose of metronidazole is excreted in the feces, 122 The elimination half-life of metronidazole in patients with no renal function is the same as in normal individuals. l5,42 During hemodialysis metronidazole is rapidly removed, and its elimination half-life is reduced to 2.6 hours. 42 With repeated doses, metabolites accumulate in anuric patients but are rapidly removed by dialysis, ·12

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These data suggest that the dosage regimen should not be modified for patients with altered renal function or for an uric patients on dialysis. In patients with impaired hepatic function, the plasma clearance of metronidazole is decreased, and a dosage adjustment may be necessary. In this clinical situation, serum levels should be monitored by either bioassay]()" or high-pressure liquid chromatography" in order to devise appropriate therapeutic regimens.

ADVERSE EFFECTS The incidence of untoward effects associated with the use of metronidazole is low. An unpleasant metallic taste, anorexia, nausea, and vomiting are occasionally experienced. I1 . 70 Furring of the tongue, glossitis, and stomatitis may occur during therapy and may be associated with overgrowth of Candida. Neutropenia, which is reversible, has rarely occurred during therapy with metronidazole.78.'36 Neurologic side effects-including sensory polyneuropathy, usually manifested by paresthesia, ataxia, and incoordination-have been reported in a few patients after prolonged treatment with high doses. The manifestations are reversible if treatment is stopped when the symptoms first occur. Convulsions and encephalopathy have been reported in association with high doses of the drug. 73 One case of colitis caused by Clostridium difficile after metronidazole administration has been reported. 117 The isolate proved sensitive to the drug at 0.25 f.lg per m!. The urine of patients taking metronidazole may be colored deep red-brown due to the presence of an azo metabolite of the drug. A factitious dcpression of serum aspartate aminotransferase (SCOT) down to zero IV, as determined by Technicon SMA-12, may occur during metronidazole therapy.107 Metronidazole produces a disulfiram-like reaction in some but not all patients who drink alcohol while taking the drug. 7o .1l3 It is good to warn patients that such a reaction may occur. An acute psychotic or confusional state may he induced if metronidazole is administered to alcoholic patients receiving disulfiram. 113 Metronidazole increases the hypoprothrominemic effect of racemic sodium warfarin (coumadin sodium) by inereasing its plasma half_life. 72 . 96 The reaction is stereospecific: It occurs with S( - )-warfarin and the racemic mixture but not with R( + )warfarin. This reaction can be lessened or even avoided if racemic warfarin is replaced by R( + )-warfarin for long-term therapy. For patients receiving both racemic warfarin and metronidazole, it is important to monitor closely the degree of hypoprothrombinemia and to adjust the dosage of warfarin as necessary.

Carcinogenicity Prolonged high-dose feeding of metronidazole to mice causes an inerease in the incidence of malignant lymphoma and pulmonary adenoma.lll.1l5 Similar studies have shown that hepatocarcinoma and mammary tumors develop in rats. 110.116 These effects, however, have not been confirmed in other animal models. 2 1.1()9 To date there is no evidence to suggest that metronidazole is carcinogenic in humans. Two retrospectic studies have shown no increase in the incidence of cancer in patients previously exposed to metronidazole. 8.41 However, these studies were conducted with relatively few patients, and the observation periods may not have been as long as the latency period of chemical carcinogenesis in humans.

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Mutagenicity Metronidazole increases the spontaneous mutation rates of certain aerobic bacteria in vitro. H2.143 However, various in vitro test systems have not implicated metronidazole as a mammalian mutagen. 1O ·5(i.74.75.1" The occurrence of congenital defects in infants born to mothers treated with metronidazole during pregnancy has been investigated in a few studies. 8H . 11O None of these studies indicated that metronidazole is teratogenic, even when exposure occurred during the first trimester. The number of patients examined, however, was insufficient to completely exclude a relatively small risk to the fetus. Metronidazole crosses the placental barrier and enters the fetal circulation. It should be used during pregnancy only if clearly needed, and it should be avoided during the first trimester. ACKNOWLEDGMENTS We wish to thank Alan M. Levensohn for his advice in the preparation of this manuscript. We are also grateful to Bernice B. Carr, P.A., for her assistance in obtaining needed references for review.

REFERENCES l. Adams, E. B.: Metronidazole in invasive amebiasis. In Finegold, S. M. (cd.): Metronidazole. Proceedings of the International Metronidazole Conference. Amsterdam, Excerpta Media, 1977, p. 87. 2. Adams, E. B., and MacLeod, I. N.: Invasive amebiasis. I: Amebic dysentery and its complications. Medicine, 56:315, 1977. 3. Adarns, E. B., and MacLeod, I. N.: Invasive arnebiasis. 11: Arnebic liver abscess and its complications. Medicine, 56:325, 1977. 4. Amon, I., Amon, K., and Huller, H.: Pharmacokinetics and therapeutic efficacy of metronidazole at different dosages. Int. J. Clin. Pharmacal., 16:384, 1978.

5. Appelbaum, P. C., Moodley, J., Chatterton, S. A., et al.: Metronidazole in the prophylaxis and treatment of anaerobic infection in patients following abdominal hysterectomy. In Phillips, I., and Collier, J. (eds.): Metronidazole. (Royal Society of Medicine International Congress and Symposium Series, No. 18). London, Royal Society of Medicine and Academic Press, 1979, p. 199. 6. Balsdon, M. J., Taylor, G. E., and Pead, L.: COr!Jnebacterium vaginale and vaginitis: A controlled trial of treatment. Lancet, 1:501, 1980. 7. Bannatyne, R. M., and Harnett, N. M.: Metronidazole and acne. Acta Derm. Venereol., 56:307,1976. 8. Beard, C. M., Noller, K. L., O'Fallon, W. M., et al.: Lack of evidence for cancer due to use of metronidazole. N. Eng!. J. Med., 301:519, 1979. 9. Bolton, R. P.: Clostridium difficile-associated colitis after neomycin treated with metronidazole. Br. Med. J., 2:1479, 1979. 10. Bost, R. C.: Metronidazole: Mammalian mutagenicity. In Finegold, S. M. (cd.): Metronidazole. Proceedings of the International Metronidazole Conference. Amsterdam, Excerpta Medica, 1977, p. 126. 11. Brass, C., Ricbards, C. K., Ruedy, J., et al.: The ellects of metronidazole on the incidence of postoperative wound infection in elective colon surgery. Am. J. Surg., 135:91, 1978. 12. Bryan, C. S., Huffman, L. J., and Delbene, V. E.: Intravenous metrouidazole therapy for Bacteroides fragilis meningitis. South Med. J., 72:494, 1979. 13. Cameron, E. W. J.: The treatment of pleuropulmonary amebiasis witb metronidazole. Chest, 73:647, 1978. 14. Catterall, R. D.: Fifteen years experience witb metronidazole. In Finegold, S. M. (cd.): Metronidazole. Proceedings of the International Metronidazole Conference. Amsterdam, Excerpta Medica, 1977, p. 107. 15. Cerat, C. A., Cerat, L. L., McHenry, M. c., et al.: Metronidazole in renal Iailure. In Fiuegold, S. M. (ed.): Metronidazole. Proceedings of the International Metronidazole Conference. Amsterdam, Excerpta Medica, 1977, p. 404. 16. Chattopadhyay, B.: Bacteroides fragilis meningitis. Lancet, 1 :1371, 1977. 17. Cbien, Y. W., and Mizuba, S. S.: Activity-electroreduction relationship of antimicrobial metronidazole analogues. J. Med. Chem., 21:374, 1978.

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18. 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, S. M. (cd.): Metronidazole. Proceedings of tbe International Metronidazole Conference. Amsterdam, Excerpta Medica, 1977, p. 286. 19. Chow, A. W., Patten, V., and Bendnorz, D.: Susceptibility ofCampylobacter fetus to 22 antimicrobial agents. Antimicrob. Agents Chemother., 13:416, 1978. 20. Churcher, G. M., and Human, R. P.: Assessment of the in vitro activity against Bacteroides spp. of spectinomycin, metronidazole and clindamycin. J. Antimicrob. Chemother., 3:363, 1977. 2l. Cohen, S. M., Enturk, E., Von Escb, A. M., et al.: Carcinogenicity of5-nitrofurans, 5-nitroimidazoles, 4-nitrobenzenes and related compounds. J. Natl. Cancer Inst., 51:403, 1973. 22. Corrodi, P., Buscb, D. F., Sutter, V. L., et al.: Factors affecting the in vitro antibacterial activity of metronidazole. In Finegold, S. M. (ed.): Metronidazole. Proceedings of tbe International Metronidazole Conference. Amsterdam, Excerpta Medica. 1977, p. 299. 23. Csonka, G. W.: Trichomonal vaginitis treated with one dose of metronidazole. Br. J. Vener. Dis., 47:456, 1971. 24. Dion, Y. M., Ricbards, G. K., Prentis, J. J., etal.: The influence of oral versus parenteral preoperative metronidazole on sepsis following colon surgery. Ann. Surg., 192:221, 19S0. 25. Dornbuscb, K., Nord, C. E., and Dahlback, A.: Antibiotic susceptibility of Clostridium species isolated from human infections. Scand. J. In!ect. Dis., 7:127, 1975. 26. Douglas-Smitb, B. J., and Wellingham, J.: Metronidazole in treatment of empyema. Br. Med. J., 1:1074, 1976. 27. Dykers, J. R., Jr.: Single-dose metronidazole for trichomonal vaginitis: Patient and consort. N. Engl. J. Med., 293:23, 1975. 2S. Edwards, D. I.: The action of metronidazole on DNA. J. Antimicrob. Cbemotber., 3:43, 1977. 29. Edwards, D. I., Dye, M., and Carne, H.: The selective toxicity of antimicrobial nitroheterocyclic drugs. J. Gen. Microbiol., 76:135, 1973. 30. Edwards, D. I., Knight, R. C., and Kantor, I.: Interaction of nitroimidazole drugs with DNA. In Siegenthaler, W., and Lutby, R. (eds.): Current Cbemotherapy. Proceedings of tbe Tenth International Congress of Chemotherapy, Volume n. Wasbington, American Society for Microbiology, 1975, p. 714. 3l. Elder, M. G., and Kane, J. L.: The pelvic tissue levels acbieved by metronidazole after single or multiple dosing-oral and rectal. In Pbillips, I., and Collier, J. (eds.): Metronidazole. (Royal Society of Medicine International Congress and Symposium Series, No. 18). London, Hoyal Society of Medicine and Academic Press, 1979, p. 5S. 32. Eykyn, S. J.: Metronidazole in the treatment of extraabdominal anaerobic infections. In Pbillips, I., and Collier, J. (eds.): Metronidazole. (Royal Society of Medicine International Congress and Symposium Series, No. IS). 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