Pharmacological properties
Antibacterial and antiprotozoal agent of the nitroimidazole derivative group. Active against Trichomonas vaginalis, Entamoeba histolytica and Giardia lamblia, bactericidal against pathogenic anaerobic bacteria, in particular Fusobacteria and Bacteroides. Inactive against aerobic microorganisms. Bacteriostatic effect is shown at a concentration of 3.1 μg/ml, bactericidal - 6.3 μg/ml, including the following bacteria: B. fragilis, B. melaninogenicus, Campylobacter fetus, C. peringens, Eubacterium, Peptococcus, Fusobacterium, Peptostreptococcus and Veilonella. In the presence of mixed flora (aerobic and anaerobic bacteria), metronidazole acts synergistically with antibiotics active against aerobic pathogens.
After intravenous infusion (over 20 min) of 500 mg of metronidazole in patients with anaerobic infections, the concentration of the drug in the blood serum is 35.2 μg/ml after 1 h, 33.9 μg/ml after 4 h and 25.7 μg/ml after 8 h. The half-life is 6-7 h. Metronidazole binds to plasma proteins to a small extent. It easily penetrates tissues, the volume of distribution is 70-95% of body weight. It reaches bactericidal concentrations in most tissues and biological fluids of the body, including the brain, cerebrospinal fluid, abscess contents, saliva, bile, genitals, amniotic fluid and breast milk. It is metabolized by side chain oxidation, hydroxylation or conjugation. The main product of metabolism is 1-(2-oxyethyl)-2-oxymethyl-5-nitroimidazole, which together with glucuronide constitutes from 40 to 50% of the substance excreted in the urine. Acidic and alcoholic metabolites of metronidazole have its activity by 50 and 30%, respectively. Within 24 hours, from 35 to 65% of all nitro derivatives of the drug are excreted in the urine. In patients with a normally functioning gallbladder, the concentration of metronidazole in the vesicular portion of bile after i.v. infusion at a dose of 500 mg is significantly higher than in the blood serum. In patients with renal failure, after repeated administration of the drug, an increase in its content in the blood serum is noted, therefore frequent administration of the drug is not recommended for the treatment of patients with acute renal failure.
Indication
Severe and life-threatening infections caused by microorganisms sensitive to the drug: intra-abdominal infections - appendicitis, cholecystitis, peritonitis, liver abscess and postoperative infections; gynecological and postpartum infections - sepsis, pelvic abscess, pelvic cellulitis, pelvic peritonitis; respiratory tract infections - destructive pneumonia, empyema, lung abscess; central nervous system infections - meningitis, brain abscess; other infections - septicemia, gas gangrene, osteomyelitis; prevention of postoperative infections caused by anaerobic bacteria; treatment of acute intestinal amebiasis and amoebic liver abscess.
Application
Adults and children over 12 years of age - 500 mg (100 ml) intravenously drip over 20 minutes at an average rate of 5 ml/min every 8 hours.
Children under 12 years of age - depending on the child's body weight, usually at the rate of 7.5 mg per 1 kg of body weight. The order and frequency of infusions remain the same as for adults: 5 ml/min for 20 minutes every 8 hours. At the first opportunity, you should switch from intravenous infusions to taking the drug orally (200-400 mg 3 times a day).
Contraindication
Hypersensitivity to metronidazole and other metronidazole derivatives.
Side effects
Anorexia, nausea, vomiting, abdominal pain, dizziness, fatigue, dark urine, rarely - ataxia, headache, transient neutropenia, metallic taste in the mouth, burning sensation in the vagina and bladder, irritation of the gastric mucosa, diarrhea, dry tongue, peripheral neuropathy, leukopenia.
Special instructions
It is not recommended to prescribe in the first trimester of pregnancy and during breastfeeding. If long-term treatment with metronidazole is necessary, it is recommended to monitor the leukocyte formula of the blood.
Interactions
Metrogyl for IV infusions should not be mixed in the same volume with other drugs. Metrogyl is chemically incompatible with 10% glucose solution, potassium salt of benzylpenicillin, Ringer's solution. It is recommended to stop taking indirect anticoagulants 24 hours before the drug is administered.
Storage conditions
Store at room temperature, protected from light. Do not freeze.
Current information
Metronidazole is one of the drugs for the treatment of anaerobic bacterial, protozoal, and microaerophilic bacterial infections.
The mechanism of action of metronidazole is as follows. The first stage is penetration by diffusion through the cell membranes of anaerobic and aerobic pathogens. The second stage is reductive activation by intracellular transport proteins by changing the chemical structure of pyruvate-ferredoxin oxidoreductases. The reduction of metronidazole creates a concentration gradient in the cell, which stimulates the absorption of a larger amount of the drug and promotes the formation of free radicals, which are cytotoxic. The third stage is interaction with intracellular targets, achieved by cytotoxic particles interacting with the DNA of the host cell, which leads to DNA strand breakage and fatal destabilization of the DNA helix. The fourth stage is the cleavage of cytotoxic products (Connor B. Weir et al., 2019).
Since metronidazole is prescribed for the treatment of bacterial infections caused by various microorganisms, let's consider the positive results of its use as part of complex therapy for infections that may occur in patients with diabetic foot syndrome.
Diabetic foot syndrome is a serious, disabling complication of diabetes. Treatment is usually expensive and can be life-threatening, leading to lower limb amputation, and can lead to systemic infection and sepsis.
This syndrome develops as a result of damage to the peripheral nervous system in diabetes mellitus, which leads to motor, sensory and autonomic neuropathy, which causes foot deformity, causes atherosclerosis of peripheral vessels. This leads to the formation of ulcers on the foot due to minor trauma. Correct and timely therapy of diabetic foot ulcers plays a crucial role in preventing the development of infection, but recurrent ulcers and infections can occur. The final result of therapy depends on wound care (dressing change, healing control), surgical intervention and drug treatment.
Before prescribing complex therapy, it is necessary to study the patient's medical history and general health at the time of therapy, assess the microcirculation of the lower extremities, the depth of the wound and identify the bacteria that influenced the development of the infection. In cases of mild foot lesions: checking the depth of the wound, drainage of the abscess, assessment of the microcirculation of the lower extremities and determining the sensitivity of microorganisms to antibacterial drugs are important components in choosing the right antibiotic treatment and preventing infection of adjacent tissues. Moderate and severe foot lesions require more aggressive surgical treatment of wounds and drainage of abscesses with minor or major amputations in some cases, these manipulations are an addition to a long-term regimen of antibacterial therapy.
To destroy all microorganisms involved in the inflammatory process, it is necessary to choose the right antibiotic. Antibiotics should be effective against S. aureus and streptococcal species that are often isolated. There are various recommendations for the choice of antibiotics. However, each treatment protocol depends on the severity of the infection, the type of isolated microorganism (bacterial culture of the wound contents for pathogenic microflora) and the medical history, previous antibiotic therapy.
research
The aim of this study was to evaluate surgical wound care and antibacterial effect in the treatment of mild to moderate diabetic foot infection. The study was conducted between October 2015 and November 2016.
It involved 60 patients with diabetic foot syndrome and osteomyelitis or without it. Patients were divided into groups as follows: group 1 - mild severity of the disease and group 2 - moderate severity. In the therapy of patients in both groups, local wound treatment and systemic administration of antibiotics were used. Patients in group 1 (16 patients) received 2 oral antibiotic regimens: regimen A (amoxicillin and clavulanic acid + metronidazole) and regimen B (clindamycin + metronidazole) for 10-14 days. Patients in group 2 (42 patients) received oral and intravenous antibiotics according to 2 regimens: regimen A (ampicillin + cloxacillin + metronidazole) and regimen B (lincomycin + metronidazole) for 6 weeks. The patients' wounds were cared for for 3 months. Further, the results of the effectiveness of therapy were assigned the following categories: complete recovery, significant improvement in indicators, or lack of positive dynamics.
Clinical data of 60 patients were displayed in special cards, they contained the following information: general information about the patient, history of diabetes mellitus, history of diabetic foot syndrome, data on previous amputation, current antibiotic therapy.
The exclusion criteria for patients from the study were severe types of infection, severe ischemia with gangrenous lesions, and the presence of diabetic foot ulcers without signs of infection.
therapy
The wounds were treated under local anesthesia, the abscesses were drained, and a wound swab was taken to further identify the pathogen and its sensitivity to antibacterial drugs. Some wounds required limited surgical resection of parts of the finger or toe followed by washing with 0.9% sodium solution, followed by the application of a gauze turunda soaked in 2% iodine solution. Wound treatment and care are important stages of initial therapy (it is necessary to drain the abscess correctly and in a timely manner and remove all necrotic tissue). Depending on the severity of the wound, dressings were changed 1-2 times a day. The patients' wounds were observed every 5 days, then every 10-14 days, for 3 months after the initial improvement was visible.
Empirical antibiotic treatment
Group 1. Patients with mild disease. Treatment regimen A: amoxicillin + clavulanic acid orally every 12 hours and metronidazole every 8 hours for 10-14 days. Treatment regimen B. This group included patients who had a history of hypersensitivity to penicillin or who had taken penicillin (during previous therapy) and no hypersensitivity reaction was observed. They were prescribed clindamycin every 6 hours and metronidazole every 8 hours for 10-14 days.
Group 2. Patients with moderate disease severity with or without osteomyelitis. Therapeutic regimen A: IV ampicillin/cloxacillin and oral metronidazole for 5 days. Then, if no positive dynamics from therapy were observed, either the same course of treatment was repeated, or the oral regimen was switched to the regimen that was similar to the prescriptions in group 1, therapeutic regimen A; the treatment period was at least 6 weeks. Therapeutic regimen B, this group included patients who had a history of hypersensitivity to penicillin or had already taken penicillin during previous therapy. They were prescribed IV lincomycin and oral metronidazole for 5 days, and then either the same course of therapy was repeated (in the absence of a positive response to treatment), or the oral regimen was switched to the regimen that was similar to the prescriptions in group 1, therapeutic regimen B; The treatment period is at least 6 weeks.
evaluation of results
According to the results of treatment, patients were divided into groups. The criterion for division was the patient's response to the prescribed therapy. The assessment of treatment results was carried out every 5 days in the acute stage (during the first 3 weeks), then every 10-14 days during the next 3 months.
Group 1 - complete recovery: all signs and symptoms of inflammation, pus, and osteomyelitis disappeared, the wound began to heal.
Group 2: incomplete relief of signs and symptoms of infection (significant improvements noted).
Group 3: lack of any positive dynamics, no improvements from the prescribed therapy were observed.
A total of 58 patients participated in this study, 2 were excluded due to the development of adverse drug reactions. Among the patients in group 1, who were prescribed therapeutic regimen A, 8 (80%) completely recovered, and 2 (20%) did not receive a positive result from the prescribed treatment regimen and switched to therapeutic regimen B in their own group. Both were cured after 14 days of therapy with regimen B. 6 (100%) patients in group 1, who received therapeutic regimen B, completely recovered after 10-14 days of treatment.
Group 2 included 42 patients, 26 of whom were assigned therapeutic regimen A: 16 fully recovered, 3 showed significant improvement, and 7 showed no positive dynamics. 16 patients were assigned therapeutic regimen B; as a result, 11 had a complete recovery, 2 had incomplete reduction of signs and symptoms of infection, and 3 had a negative outcome.
Adverse reactions were recorded, including diarrhea and skin rashes, which occurred in 2 patients from group 1. Therefore, an urgent change of treatment regimen was necessary. Most patients tolerated antibiotic therapy well with minor and reversible gastrointestinal disorders.
Results of bacterial culture and determination of sensitivity of pathogenic microflora to antibiotics: Gram-positive pathogens (staphylococci and streptococci) were detected in 21 patients. Most had a mixed infection; 3 patients had Escherichia coli, 1 had Pseudomonas.
The observation period of the patients lasted for 3 months, including local wound care every 10-14 days (after completion of the antibiotic regimens). As a result, no relapse was noted in the completely recovered patients; 3 patients with visible improvements due to therapy fully recovered at the end of the observation period. 2 patients had to repeat the antibiotic regimen; but all attempts at additional therapy resulted in amputation of the limb.
conclusions
This study used inexpensive, broad-spectrum antibiotics that have been prescribed for many years, have well-known and predictable side effects, and can be administered on an outpatient basis.
The complete cure rate in group 1 was 87.5%, which is acceptable since the patients did not have osteomyelitis and had an immediate positive response to the selected antibiotics. These results are consistent with other studies that evaluated the efficacy of clindamycin and cephalosporin for the treatment of diabetic foot infections caused by Staphylococcus aureus and gram-negative organisms, with a success rate of 87%.
Metronidazole was administered to patients in both groups in 2 therapeutic regimens, as it is well tolerated and provides antimicrobial activity against most anaerobic microorganisms.
This explains the low incidence of adverse reactions observed during treatment; adverse reactions occurred in only 2 patients in the group receiving oral clindamycin.
In group 2, the complete recovery rate was 64.28% with both treatment regimens; 20 patients developed osteomyelitis, which probably affected the success of the treatment. However, 35% of patients with osteomyelitis were cured, and 20% showed improvement during 6 weeks of antibiotic therapy, and none of them had relapses during the 3-month follow-up period. There was no need for hospitalization or additional costs.
Analysis of treatment failures revealed that most of them were caused by uncontrolled blood glucose levels, despite endocrinological consultation; however, this was mainly due to the low socioeconomic status of most patients.
conclusion
Combined therapy of patients treated with surgery and combined therapy with antibiotics and metronidazole resulted in high rates of complete recovery during the study period with lower monetary costs and hospitalization rates. Proper wound care and observation increased the proportion of complete recovery and reduced the duration of antibiotic treatment. Oral clindamycin and metronidazole resulted in higher rates of complete recovery in patients with mild disease, while intravenous lincomycin and oral metronidazole demonstrated higher rates of complete recovery in patients with moderate disease with or without osteomyelitis (Aliakbar AH et al., 2019).
