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 (1g orally as single dose, 200mg 8 hourly thereafter when possible and 1g 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).