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Department of Pediatrics, TSMU
Modern medicine is rich in antibacterial preparations. The most famous and widely used antibiotics’ group is penicillin and its derivatives. Penicillins belong to β-lactam antibiotics’ group (β-lactams), because their molecular structure contains so called β-lactam ring. Following antibiotics belong to β-lactam group: penicillins, cephalosporins, carbapenems, monobactams. They are used for treatment of bacterial infections. Their mechanism of action is bactericidal, which is fulfilled by disturbing a process of bacterial cell wall synthesis. In result, osmotic pressure regulation is damaged in microorganism and water diffuses into the cell, which swells and at last bursts.
Peptidoglycan layer plays important role in maintenance of structural integrity of bacterial cell wall. The final step of its synthesis is conducted via ferment transpeptidase, which is known as penicillin binding protein.
β-lactam antibiotics have analogical structure to terminal amino acids D-alanin-D-alanin of the precursor of bacterial cell wall peptidoglycan layer. Because of this similarity in structure, β-lactam antibiotics bind to the active end of the penicillin binding protein and irreversibly tie-up it by their β-lactam ring. Blockage of penicillin binding protein prevents formation of peptidoglycan layer and bacterial cell wall synthesis is prevented.
Normally, for the reorganization process of bacterial cell wall, precursor of peptidoglycan layer is activated and hydrolysis of cell wall is enhanced “. Blockage of penicillin binding protein by β-lactam ring conditions incorrect information to the precursors. They stimulate hydrolysis of preformed peptidoglycan layer, without production of new chains. In the result bactericidal action of the antibiotic is enhanced.
Hence, effectiveness of action of antibiotics of mentioned group is conditioned by their ability to bind penicillin binding protein.
There are two main directions of development of resistance, to this group of antibiotics.
First is fermentic hydrolyses of β-lactam ring. If bacteria produce ferment β-lactamase that is penicillinase, it destructs β-lactam molecule of the drug, consequently it do not bind penicillin binding protein any more, synthesis of bacterial cell wall is not prevented and antibiotic is ineffective against this particular bacteria. This ferment is produced by many microorganisms, which decrease effectiveness of penicillins and cephalosporins against wide variety of microorganisms.
The second kind of resistance is related to the presence of changed form of PBP. In such case, β-lactam antibiotics can not bind to the changed penicillin binding protein effectively and hence are less effective against these microorganisms. Combinations of β-lactams and β-lactamase inhibitors is produced and used effectively to increase of effectiveness of β-lactam antibiotics and to avoid development of resistance of β-lactamase producing bacteria to them. β-lactamase inhibitors possess weak antimicrobial effect, but they are potent inhibitors of bacterial ferment - β-lactamase, this fact gives us opportunity to use β-lactamase inhibitors successfully in combinations with β-lactam antibiotics. β-lactamase inhibitors are: sulbactam, clavulanic acid and tazobactam
Antibiotic Bactamed is combined by wide spectrum, semi-synthetic penicillin- ampicillin sodium and β-lactamase inhibitor - sulbactam. Ampicillin is active against following gram-positive microorganisms: Staphylococcus spp. (except the strains which produce penicillinase), Streptococcus spp. (Enterococcus), Listeria monocytogenes, Corynebacterium diphtheriae. Ampicillin is also active against gram- negative microorganisms: Neisseria gonorrhoeae, Neisseria meningitidis, Moraxella catarrhalis, Haemophilus influenzae, Bordetella pertussis, Escherichia coli, Shigella spp., Salmonella spp., Proteus mirabilis, Proteus vulgaris,. Providencia spp., Aeromonas spp., Brucella spp., Pasteurella multocida, Haemophilus ducreyi. Ampicillin, as the classic representative of β-lactam antibiotics binds and blocks penicillin binding protein on the inner surface of bacterial cell wall, which leads to blockage of peptidoglycan chain synthesis and causes destruction of bacterial cell wall and eventually the microorganism.
The second component of Bactamed, so called “antibiotic” irreversibly binds active end of bacterial β-lactamase, blocks it and hence interrupts harmlessness of bactericidal effects of ampicilline. Correspondingly combination of two antibiotics in Bactamed widens its antimicrobial spectrum and resists development of bacterial resistance to this medication.
Sulbactam has relatively weak, but still antibacterial action against the following microorganisms: Neisseriaceae, Acinetobacter calcoaceticus, Bacteroides spp., Branhamella catarrhalis, and Pseudomonas cepacia. Due to synergistic action of two antibiotics combined medication Bactamed is distinguished by its wide antimicrobial spectrum.
Urinary tract infections are at the second place after respiratory infections in the list of childhood diseases. It contributes to 1-5 % of all outpatient and 40% of all inpatient cases. Urinary tract infections are met in children of all age groups: more frequently in boys in first 6 month, with equal frequency in girls and boys from 6 month to 5 years age group and twice as often in girls than boys after 5 years of age.
What about the etiology of the disease: the main causative of urinary tract diseases is Escherichia coli - 75%-80% in all cases. Following microorganisms also take the important place in the etiology of UTDs: Staphylococcus spp., 5%-15%, Klebsiella, Enterococci, Proteus mirabilis 5%-10%, Ureaplasma urealiticum, Mycoplasma hominis, Pseudomonas aeruginosa.
Development of the disease has two main pathologic mechanisms, which causes disturbance of natural barrier mechanisms of the urinary tract and bacterial growth.
One pathologic mechanism is disturbance of acid-base balance of the urine. Natural flora of urinary tract - Lactobacilli normally contributes to maintenance of acid pH in the tract. Decrease of their contents in the tract, conditioned by different causes, because rise in pH to the basic medium which contributes to bacterial growth and spreading of infection.
The second mechanism is ability of some bacteria to encapsulate, attach to the wall and protect themselves from the inconvenient medium.
Based on the course of the disease, it is classified in uncomplicated and complicated forms. Uncomplicated are infections which do not cause disturbance in urodynamics, is not accompanied by structural and functional changes of kidneys and when there is not revealed any developmental anomalies of the urinary tract. Correspondingly complicated cases cause disturbance in urodynamics and is accompanied by morphological changes of kidneys. E.coli is identified only in 40-50% of such cases, in other cases causatives may be Pseudomonas aeruginosa - 23%, Enterococcus spp. – 12% etc.
Based on the mentioned above, treatment of urinary tract infections in children still remains the serious problem. Treatment is directed to interrupt bacterial growth, to prevent generalization of infection and development of exacerbations. The final one represents no less serious problem, than previous.
The treatment strategy depends on: child’s age, the form of the disease (complicated or uncomplicated), localization of the process, severances of the infection. Following should be taken in view before the treatment:
1.      Etiotrophy of the medication, taken in view sensitivity of the causative.
2.      Choosing the optimal dose
3.      Prompt initiation of the treatment
4.      Rapid change of antibacterial preparation upon development of bacterial resistance
5.      Rational combination of antibacterial preparations.
Treatment principle is,,from simple to complex”. This prevents development of resistant strains and ensures therapeutic effectiveness in case of complications.
Based on the etio-pathogenesis of the disease, first line medication for treatment of urinary tract infections are considered to be beta-lactam antibiotics. They are characterized by wide spectrum of action and low toxicity.
Combined beta-lactam antibiotic Bactamed is the first line preparation for treatment of inpatient urinary tract infections. It is important to mention its effectiveness in treatment of pyelonephritis, especially in newborns when the disease is spread hematogenously. This is conditioned by fact that Bactamed has wide antibacterial spectrum of activity, reaches high concentration in serum and in renal parenchyma, and is not characterized by nephro-toxicity in contrast to aminoglycosides. The main part of the drug is excreted by kidney, so it is possible to create high concentration of antibiotic in urinary tract and urine, and this ensures its effectiveness in treating urinary tract infections. Usage of I and II generation of cephalosporins is not recommended because they are ineffective against gram negative bacteria. Cotrimoxazole is less effective against E.coli and nitrofurans do not reach high concentration in renal parenchyma.
Recommended dose regime for newborns and infants is: Bactamed 0,75 g for injection divided for 2 doses. For children 1 to 5 years age it is normal to use 0,75 or 1,5 g Bactamed twice daily depending on the severity of the condition, for children older than 5 years 1,5 g Bactamed twice daily is recommended.
Treatment of outpatient lower urinary tract infections (cystitis, uretritis) may be began with per os use of ,,resistant” penicillins – (Clavomed); less effectives are cephalosporins, cotrimaxazole, nitrofurans.
Preparation Bactamed is successfully used in TSMU clinic, named G.Jvania for treatment of LOR-infections, pneumonias, urinary tract infection, and generalized infections independently and in combination with other preparations.