Antibiotic therapy of angiogenic sepsis

Introduction to medical practice of new penicillins, cephalosporins and aminoglycosides is one of the chief reserves for increasing efficacy of antibacterial therapy. The main schemes of antibiotic use in treatment of sepsis and individual regimens controlled by laboratory findings are discussed. Optimization of antibiotic therapy schemes is based on pharmacokinetic studies, quantitative assay of antibiotic sensitivity and determination of antibacterial activity of serum and other biosubstrates at definite periods after antibiotic administration. In vitro time course investigation of the bactericidal effect of gentamicin, azlocillin and cefotaxime on pathogens of purulent infections at various sizes of the inoculum provided prediction of the antibiotic therapy efficacy in various purulent septic infections. It is indicated that rational use of antibiotics markedly increases efficacy of sepsis therapy and improves social and economic indices of the treatment.     

Side effects of antibiotics in patients with thermal burns]

The possibilities of antibacterial therapy in the clinics of burn diseases has at present decreased because of increasing microflora resistance to antibiotics. This phenomenon is one of the most often causes of antibacterial drug side effects in burn patients. For control of infections complications in burn patients which are most often lethal it is necessary to use biologically active subtance, such as prodigiozan and lysozime in addition to the directed antibiotic therapy. The use of specific antitoxic antistaphylococcal drugs, such as antistaphylococcal plasma and antistaphylococcal gamma-globulin in combination with the antibiotics of the direct action provided effective control of infectious complications and sepsis of staphylococcal genesis in burn patients. Decamine proved to be effective along with the usual use of nystatin in cases with dysbacteriosis as a result of the antibiotic side effects. In the patients treated with decamine the sings of candidosis disappeared by the 5th--7th day. Therefore, for decreasing the side effects of antibiotics in the clinics of burn patients it is expedient to use antibiotics in combination with the biologically active and immune preparations which increases the efficacy of antibiotic therapy, impfoves the treatment results and decreases the antibiotic side effects.     

Effectiveness of acipole in prevention of enteric dysbacteriosis due to antibacterial therapy]

Acipole (Lactobacillus acidophilus + Kefir greins) was used to manage antibiotic dysbacteriosis as an adverse reaction of antibacterial therapy. 120 patients treated with antibacterial drugs for acute pneumonia and exacerbations of chronic bronchitis were observed. 54 of them were treated under the routine regimen with antibiotics and 66 were additionally treated with the eubiotic acipole: 1 tablet (5 doses) 3 times a day 30 minutes before meal. Routine bacteriological examination of the feces was applied to all the patients. High frequency of bacteriologically revealed dysbacteriosis was stated. The therapy under the antibiotic + acipole regimen lowered the frequency of dysbacteriosis events and their severity. The fact that the use of acipole simultaneously with the routine antibacterial therapy prevented the development of dysbacteriosis clinical signs is of practical importance.     

Intestinal dysbacteriosis in antibacterial therapy and perspectives in treatment by antibiotic-resistant probiotics]

Effect of different antibiotics and standard antibacterial therapy regimes on intestine microflora was investigated. Lincozamides demonstrated the most negative effect. Early addition of probiotics to the treatment with antibacterials had positive effect. Susceptibility of 21 strains of normal microflora to 25 antibiotics was tested. Resistance to antibiotics of lactobacilli varied significantly (more among strains and less among species). It was shown that L. acidophilus (probiotic "Acilact") was resistant to metronidazole only. High resistance to antibiotics was shown for L. plantarum 8RA3, L. fermentum 90T4C (components of probiotic "Lactobacterin"), L. fermentum BL96, L. acidophilus BL and L. acidophilus (component of "Linex"). Susceptibility of microorganisms in complex formulation "Linex" to the modern antibiotics was low. It is concluded that the use of stable antibiotic-resistant strains of normal microflora is favorable as addition to antibiotic therapy.     

Investigating reaction pathways in rare events simulations of antibiotics diffusion through protein channels

In Gram-negative bacteria, outer-membrane protein channels, such as OmpF of Escherichia coli, constitute the entry point of various classes of antibiotics. While antibacterial research and development is declining, bacterial resistance to antibiotics is rising and there is an emergency call for a new way to develop potent antibacterial agents and to bring them to the market faster and at reduced cost. An emerging strategy is to follow a bottom-up approach based on microscopically founded computational based screening, however such strategy needs better-tuned methods. Here we propose to use molecular dynamics (MD) simulations combined with the metadynamics algorithm, to study antibiotic translocation through OmpF at a molecular scale. This recently designed algorithm overcomes the time scale problem of classical MD by accelerating some reaction coordinates. It is expected that the initial assumption of the reaction coordinates is a key determinant for the efficiency and accuracy of the simulations. Previous studies using different computational schemes for a similar process only used one reaction coordinate, which is the directionality. Here we go further and see how it is possible to include more informative reaction coordinates, accounting explicitly for: (i) the antibiotic flexibility and (ii) interactions with the channel. As model systems, we select two compounds covering the main classes of antibiotics, ampicillin and moxifloxacine. We decipher the molecular mechanism of translocation of each antibiotic and highlight the important parameters that should be taken into account for improving further simulations. This will benefit the screening and design for antibiotics with better permeation properties.     

A novel approach for assessing the susceptibility of Escherichia coli to antibiotics

The dynamic growth process of Escherichia coli CVCC249 under different concentrations of antibiotics was analyzed. The results suggested that the main reason that definitive results cannot be obtained by antibiotic susceptibility testing (AST) is that the ratio of drug concentration to the population of bacteria and the combined effect of drug concentration and action time cannot be completely determined with the methods used. Based on the analysis of the growth process with a series of concentrations of gentamicin acting for a certain time, and according to the forward difference method, a novel method for AST was proposed. The net increase in turbidity of the bacterial population was used to eliminate the existing effects of resting cells, and then the recurrent coefficient for a growing sequence was used to characterize the effect of antibiotics on bacterial division, and the contour plot was used to display and analyze the combined effect of drug concentration and action time. The inhibition rate of the antibiotics can be characterized as the dynamic change in the composite function of the antibiotic concentration and action time, which indicated that the inhibition rate was dependent on the combined effect of time and concentration of antibiotics. The effectiveness of this new method has been verified with different kinds of antibiotics, such as enrofloxacin, levofloxacin, and ceftriaxone, having different antibacterial mechanisms.     

Intralymphatic administration of antibiotics in the complex treatment of suppurative complications in patients with neurosurgical pathology

The efficacy of endolymphatic route of gentamicin and ceporin administration was studied in 89 patients with neurosurgical pathological processes complicated by acute pneumonia (80 patients) and meningoencephalitis (9 patients) usually after ineffective antibiotic therapy according to the routine methods. The antibiotics were used in accordance with the antibiograms of the causative agents isolated from the bronchial tree or CSF. The endolymphatic use of gentamicin or ceporin once a day in doses of 80 mg or 1 g respectively provided rapid sanation and arresting of the inflammatory foci, lowering of the intoxication level, more rapid promotion of the positive time course of the clinico-roentgenological and laboratory indices and decreasing of the recovery periods by 1.5-2 times in 86 per cent of the patients with pneumonia. The endolymphatic administration of gentamicin in a dose of 80 mg twice a day or ceporin in a dose of 1 g twice a day allowed one to maintain the antibiotic therapeutic levels in the cerebrospinal fluid and to obtain satisfactory clinical results in the combined treatment of meningoencephalitis. The endolymphatic administration of the drugs was well tolerated by the patients and no adverse reactions were observed. This route of administration of antibiotics and in particular broad spectrum antibiotics may be recommended for urgent antibacterial therapy of especially severe neurosurgical patients with pyo-inflammatory complications and patients who did not respond to the routine antibiotic therapy.     

Detection of persistent resistance to antibacterial drugs in various strains of Francisella tularensis]

Under natural conditions, the Francisella tularensis strains AE-261 and P-13864 capable of forming the persist type of resistance to antibacterial drugs and being the cause of the infection in laboratory animals not responding to monotherapy with antibiotics were detectable. The antibioticograms of strains AE-261 and P-13864 under the in vitro conditions did not differ from those of the other studied strains responding to the antibiotic therapy. The observed phenomenon could be associated with individual peculiarities of the strains and their phenotypic variation in the host. Combinations of aminoglycoside antibiotics (streptomycin, gentamicin and amikacin) with rifampicin were shown to be highly active in the treatment of general forms of the infection due to such strains. The combined therapy of tularemia was also considered promising because of its high efficacy when the treatment was started at late periods as well as because unlike the monotherapy with the aminoglycoside antibiotics it provided complete elimination of the pathogen from the host.     

Participation of the antibiotics of Bac. pumilus and Bac. subtilis in the regulation of bacterial spore formation]

Sporulation and antibiotic production, as well as the effect of exogenic antibacterial substances on bacterial sporogenesis were studied in various strains of Bac. pumilus and Bac. pumilus and Bac. subtilis. The bacteria were grown on a solid sporulation medium with and without the antibiotics. After 5-day incubation the presence of refractyl spores was determined with a phase-contrast method. It was found that in the strains of Bac. pumilus producing antibacterial substances the sporulation was normal. The loss of the capacity for synthesizing such substances resulted in asporegenicity or oligosporogenicity. This allowed a conclusion on existence of phenomenological connection between sporulation and antibiotic production. The study of the antibiotic effect on bacterial sporogenesis showed negative results which are discussed in the paper along two directions: (1) the antibiotics did not probably participate in regulation of the bacteria cell differentiation, (2) the antibiotics regulated the bacterial sporogenesis though their effect was not as yet detected because of methodical difficulties. Therefore, the problem of the antibiotic participation in regulation of sporulation in Bac. pumilus and Bac. subtilis remains open.     

The within-host population dynamics of normal flora in the presence of an invading pathogen and antibiotic treatments

A mathematical competition model between normal flora and an invading pathogen was devised to allow analysis of bacterial infections in a host. The normal flora includes the various microorganisms that live on or within the host and act as a primary human immune system. Despite the important role of the normal flora, no mathematical study has been undertaken on models of the interaction between it and invading pathogens against a background of antibiotic treatment. To quantify key elements of bacterial behavior in a host, pairs of nonlinear differential equations were used to describe three categories of human health conditions, namely, healthy, latent infection, and active infection. In addition, a cutoff value was proposed to represent the minimum population level required for survival. The recovery of normal flora after antibiotic treatment was also included in the simulation because of its relation to human health recovery. The significance of each simulation parameter for the bacterial growth model was investigated. The devised simulation showed that bacterial proliferation rate, carrying capacity, initial population levels, and competition intensity have a significant effect on bacterial behavior. Consequently, a model was established to describe competition between normal flora and an infiltrating pathogen. Unlike other population models, the recovery process described by the devised model can describe the human health recovery mechanism.     

An antimicrobial removal device as an alternative to membrane filtration in the sterility testing of antibiotics

An Antimicrobial Removal Device (ARD) is proposed as an alternative to membrane filtration in the sterility testing of antibiotics. The device consists of a glass vial containing adsorbent resins which completely removed the antibacterial activity of a range of antibiotics without affecting the recovery of contaminating bacteria. The method is simple to use and has several advantages compared to membrane filtration including easier aseptic handling and lack of antibiotic carry-over to subculture media. A problem with resin turbidity in subculture media was overcome by the use of an indicator medium or by subculture into fresh medium.     

Effects of dietary antibiotics on intestinal microflora in broiler chickens

Changes were examined in the intestinal microflora in broiler chickens fed a diet containing antibiotics to obtain fundamental information on the mechanisms of beneficial effect of the antibiotics upon livestock production. Three antibiotics (colistin, bacitracin, and enramycin) were employed as feed additives. Experiments were conducted with broiler chickens in two ways. In one way dietary antibiotics were fed continually at levels approved for use as feed additives for a long term. In the other they were fed the same antibiotics for a short term. Significant changes in microflora were observed mainly in such bacterial groups as aerobic bacteria and Lactobacillus. In the long term administration, three possible modes of variance in the bacterial flora were postulated: Changes directly related to the antibacterial spectrum of antibiotics. Antagonistic changes related to an ecological balance in the bacterial flora. Changes in quantitative balance of bacteria constituting each bacterial group. The change in the intestinal microflora during administration of the antibiotic diet was expressed as a complex form of these transition modes. In the short term administration, it was demonstrated that the effect of the antibiotic diet lingered even 7 days after administration. This suggests that antibiotics used as feed additives may possibly affect the stability of the intestinal microflora.     

Optimal combined use of rifampicin and immunomodulator of microbial origin in experimental Q-Rickettsia infection

Multifactorial analysis of the combined use of rifampicin and an immunomodulator of the microbial origin, such as peptidoglycan, was performed on a model of experimental Q fever in albino mice. On the basis of the experimental results, statistic polynomial models describing the weight of the murine spleens and the titers of the complement-binding antibodies were designed. It was shown that the action of the immunomodulator and antibiotic was highly synergistic with respect to the chemotherapeutic activity and antibody titers. The preventive use of the immunomodulator yielded a 30-fold decrease in a rifampicin therapeutic dose. The use of the immunomodulator also provided a pronounced immunomodulating effect with respect to humoral immunity. Nomographs for optimizing the dose-time parameters of the antibacterial and immunomodulating therapy were plotted.     

Ways of increasing the effectiveness of antibacterial therapy in newborns

Ways for increasing antibiotic therapy efficacy in newborns are discussed. They are the following: consideration of the structure of the antibiotic use, improvement of infection diagnosis, the use of computers in epidemiological supervision of antibiotic resistance, the use of "old" antibiotics in new dosage forms, pharmacokinetic monitoring. The data on the frequency of the antibiotic use in newborns in maternity hospitals, at home and in neonatal departments as well as on diagnosis and treatment of chlamydiosis in newborns are presented. Requirements to the computer programs on control of antibiotic resistance are described. With the account of the requirements an original epidemiological program for personal computers was developed. The results of the pharmacokinetic monitoring of the use of sisomicin and amikacin are presented as well.     

Combined Antibiotic Therapy

The indications for combined antibiotic therapy are reviewed, and two major indications are discussed at length: the prevention of development of antibiotic resistance and the possibility of achieving antibiotic synergism.Since micro-organisms vary in their behaviour in the presence of different antibiotic combinations, careful evaluation of clinical response and close laboratory control are necessary.Antibiotics are divided into four groups and their possible combinations are described. It is emphasized that bactericidal antibiotics, e.g. penicillin and streptomycin, which act only on multiplying bacteria, may be antagonized by some bacteriostatic antibiotics, e.g. tetracycline. Clinical observations appear to confirm the usefulness of this division of the antibiotics.     

Some ways to eliminate the side effects of antibiotic therapy in experimental pneumonia]

Impairement in the process of tissue respiration at the subcellular level in growing animals with experimental pneumonia are described. Under the conditions of antibiotic therapy such impairements aggravated. A combined use of antibiotics with succinic and glutamic acids resulted in improvement of the tissue respiration and acceleration of reparation. Possible mechanisms of this phenomenon are discussed.     

Microbial fuel cell-based diagnostic platform to reveal antibacterial effect of beta-lactam antibiotics

Beta-lactam antibiotics comprise the largest group of antibacterial agents. Due to their bactericidal properties and limited toxicity to humans they are preferred in antimicrobial therapy. In most cases, therapy is empiric since susceptibility testing in diagnostic laboratories takes a relatively long time. This paper presents a novel platform that is based on the microbial fuel cell (MFC) technology and focuses on the early antibiogram determination of isolates against a series of beta-lactam antibiotics. An advantage of the system is that it can be integrated into traditional microbiological diagnostic laboratory procedures. Tested bacterium suspensions are uploaded into the anodic chambers of each miniaturized MFC unit integrated into a panel system, containing different antibiotic solutions. Electronic signals gained in each MFC unit are continuously monitored and are proportional to the metabolic activity of the presenting test bacterium. Using this method, antibiotic susceptibility can be evaluated in 2–4 h after inoculation. Hereby we demonstrate the efficacy of the platform in antibiogram determination by testing the susceptibilities of Escherichia coli strain ATCC 25922 and Staphylococcus aureus strain ATCC 29213 against 10 beta-lactam antibiotics (penicillin, ampicillin, ticarcillin, cefazolin, cefuroxime, cefoperazone, cefepime, cefoxitin, cefaclor, imipenem). This paper also presents the construction of the background instrumentation and the panel system into which a printed circuit board (PCB) based electrode was integrated. Our results suggest that MFC based biosensors have the potential to be used in diagnostics for antibiogram determination.     

Etiology and rational therapy of severe otitis media purulenta acuta in children]

Etiology and antibiotic susceptibility of the pathogens of otitis media purulenta acuta in children was studied within 2000-2005. A total of 161 children at the age of 1 to 14 years were examined. The middle ear discharge collected during paracentosis (79.5%) or spontaneous perforation of the tympanic membrane (20.5%) was used in the bacteriological tests. The microflora growth in the culture was detected in 80% of the cases. The leading pathogen was Streptococcus pyogenes (47.5%), the part of Streptococcus pneumoniae amounted to 36.6% of all the etiologically significant microflora, the part of Staphylococcus aureus amounted to 6.9% and that of Haemophilus influenzae amounted to 4.0%. The part of the associations of 2 microorganisms equaled 5.0%. The species composion of the pathogens differed from that described in the literature. The isolates of S. pneumoniae and S. pyogenes were characterized by low resistance to macrolides (4.0-6.3%). As for the S. pneumoniae isolates, 97.3% of them was susceptible to penicillin. The results of the etiology study and the pathogen antibiotic susceptibility showed that the drugs of choice for the empirical antibacterial therapy of otitis media purulenta acuta in children should be amoxicillin and 1st generation cepholosporins. When the antibacterial therapy within the first 3 days fails, it is advisable to use protected aminopenicillins or 2nd generation cephalosporins. In case of the drug intolerance, macrolide antibiotics should be used.