Combined chemotherapy of experimental infection in neutropenia

A significant decrease in resistance to infections caused by gramnegative pathogens was observed in mice with neutropenia induced by cytostatics. Efficacy of schemes for combined chemotherapy with beta-lactams, aminoglycosides and a novel peptide antibiotic was studied on model infections in mice with neutropenia. In the neutropenic mice with sepsis caused by Pseudomonas the peptide antibiotic administered parenterally in a single dose of 50 micrograms/kg provided high therapeutic activity. In combination with azlocillin, cefotaxime and amikacin the peptide antibiotic has a synergistic therapeutic action.     

Central role of quorum sensing in regulating the production of pathogenicity factors in Pseudomonas aeruginosa.

Pseudomonas aeruginosa is an important opportunistic human pathogen, causing various infections that are often very persistent. P. aeruginosa infections are the major cause of death in cystic fibrosis patients. Infections are difficult to treat since P. aeruginosa is resistant to most antibiotics and its antibiotic susceptibility is decreased when it is present in biofilms. P. aeruginosa produces many exoproducts (including toxins and hydrolytic enzymes) that are involved in virulence. Recent research has elucidated many mechanisms and pathways that regulate the production of these virulence factors. The regulation is extremely complex and many components are influenced by environmental conditions. Quorum sensing is a key regulatory system, which itself is affected by many other regulators. Targeting the regulation of pathogenicity factors provides a novel strategy for combating P. aeruginosa infections. Degradation of acyl homoserine lactones, the signaling molecules of the quorum-sensing system, is a promising therapeutic treatment option.     

THE EXPERIMENTAL AND CLINICAL USE OF POLYMYXIN,CHLOROMYCETIN, AND AUREOMYCIN

Polymyxin is an effective antibiotic for the treatment of severe infections produced by Ps. aeruginosa, H. pertussis, H. influenzae, E. coli, and A. aerogenes. Its toxicity to date precludes its general use in infections susceptible to its therapeutic effects.Chloromycetin has been demonstrated to be an effective antibiotic agent for the treatment of rickettsial diseases and typhoid fever. It will undoubtedly prove effective in the treatment of other infections produced by certain Gram-negative micro-organisms and viral agents.Aureomycin has been shown to be an active antibiotic agent against rickettsial diseases, primary atypical pneumonia, acute brucellosis, pneumococcal, streptococcal, and staphylococcal infections, urinary tract infections produced by E. coli, A. aerogenes and Strept. fecalis, certain types of infections of the eye, and in subacute bacterial endocarditis when the infecting agent is Strept. fecalis. Its clinical use in forms of extrapulmonary tuberculosis is in a completely experimental stage. It is not recommended in typhoid fever or in infections due to Ps. aeruginosa or P. vulgaris, and it seems to be ineffective in whooping cough.To date, neither chloromycetin nor aureomycin has shown significant signs of systemic toxicity.     

The experimental and clinical use of polymyxin,chloromycetin, and aureomycin

Polymyxin is an effective antibiotic for the treatment of severe infections produced by Ps. aeruginosa, H. pertussis, H. influenzae, E. coli, and A. aerogenes. Its toxicity to date precludes its general use in infections susceptible to its therapeutic effects. Chloromycetin has been demonstrated to be an effective antibiotic agent for the treatment of rickettsial diseases and typhoid fever. It will undoubtedly prove effective in the treatment of other infections produced by certain Gram-negative micro-organisms and viral agents. Aureomycin has been shown to be an active antibiotic agent against rickettsial diseases, primary atypical pneumonia, acute brucellosis, pneumococcal, streptococcal, and staphylococcal infections, urinary tract infections produced by E. coli, A. aerogenes and Strept. fecalis, certain types of infections of the eye, and in subacute bacterial endocarditis when the infecting agent is Strept. fecalis. Its clinical use in forms of extrapulmonary tuberculosis is in a completely experimental stage. It is not recommended in typhoid fever or in infections due to Ps. aeruginosa or P. vulgaris, and it seems to be ineffective in whooping cough. To date, neither chloromycetin nor aureomycin has shown significant signs of systemic toxicity.     

Public Health Risks of Multiple-Drug-Resistant Enterococcus spp. in Southeast Asia

Enterococci rank as one of the leading causes of nosocomial infections, such as urinary tract infections, surgical wound infections, and endocarditis, in humans. These infections can be hard to treat because of the rising incidence of antibiotic resistance. Enterococci inhabiting nonhuman reservoirs appear to play a critical role in the acquisition and dissemination of antibiotic resistance determinants. The spread of antibiotic resistance has become a major concern in both human and veterinary medicine, especially in Southeast Asia, where many developing countries have poor legislation and regulations to control the supply and excessive use of antimicrobials. This review addresses the occurrence of antibiotic-resistant enterococci in Association of Southeast Asian Nations countries and proposes infection control measures that should be applied to limit the spread of multiple-drug-resistant enterococci.     

Therapeutic approaches for combating Pseudomonas aeruginosa infections

Pseudomonas aeruginosa is an opportunistic pathogen responsible for acute hospital-acquired infections. This review described various therapeutic approaches to treat infections caused by P. aeruginosa, including conventional therapy, novel antibiotic treatments and treatments other than antibiotics. Most of the developments are still in research that will provide novel treatment options in future.     

Comparative assessment of the therapeutic drug targets of C. botulinum ATCC 3502 and C. difficile str. 630 using in silico subtractive proteomics approach

Growing antimicrobial resistance of the pathogens against multiple drugs posed a serious threat to the human health worldwide. This fueled the need of identifying the novel therapeutic targets that can be used for developing new class of the drugs. Recently, there is a substantial rise in the rate of Clostridium infections as well as in the emergence of virulent and antibiotic resistant strains. Hence, there is an urgent need for the identification of potential therapeutic targets and the development of new drugs for the treatment and prevention of Clostridium infections. In the present study, a combinatorial approach involving systems biology and comparative genomics strategy was tested against Clostridium botulinum ATCC 3502 and Clostridium difficile str. 630 pathogens, to render potential therapeutic target at qualitative and quantitative level. This resulted in the identification of five common (present in both the pathogens, 34 in C. botulinum ATCC 3502 and 42 in C. difficile str. 630) drug targets followed by virtual screening–based identification of potential inhibitors employing molecular docking and molecular dynamics simulations. The identified targets will provide a solid platform for the designing of novel wide-spectrum lead compounds capable of inhibiting their catalytic activities against multidrug-resistant Clostridium in the near future.     

Antibiotic resistance in Pseudomonas aeruginosa: mechanisms and alternative therapeutic strategies

Pseudomonas aeruginosa is an opportunistic pathogen that is a leading cause of morbidity and mortality in cystic fibrosis patients and immunocompromised individuals. Eradication of P. aeruginosa has become increasingly difficult due to its remarkable capacity to resist antibiotics. Strains of Pseudomonas aeruginosa are known to utilize their high levels of intrinsic and acquired resistance mechanisms to counter most antibiotics. In addition, adaptive antibiotic resistance of P. aeruginosa is a recently characterized mechanism, which includes biofilm-mediated resistance and formation of multidrug-tolerant persister cells, and is responsible for recalcitrance and relapse of infections. The discovery and development of alternative therapeutic strategies that present novel avenues against P. aeruginosa infections are increasingly demanded and gaining more and more attention. Although mostly at the preclinical stages, many recent studies have reported several innovative therapeutic technologies that have demonstrated pronounced effectiveness in fighting against drug-resistant P. aeruginosa strains. This review highlights the mechanisms of antibiotic resistance in P. aeruginosa and discusses the current state of some novel therapeutic approaches for treatment of P. aeruginosa infections that can be further explored in clinical practice.     

新抗生素莫西沙星国内外研究应用最新进展

莫西沙星(moxifloxacin)属第四代氟喹诺酮类抗菌药物。莫西沙星通过抑制细菌的DNA螺旋酶A亚单位和拓扑异构酶IV的活性,阻断DNA的复制,从而发挥杀菌作用。对革兰阴性菌、阳性菌均有强大的抗菌能力,对支原体、衣原体、军团菌有效,对厌氧菌感染有效,尤其对某些临床常见的耐药菌有效。临床应用莫西沙星治疗社区获得性肺炎、急性细菌性鼻窦炎、泌尿生殖系感染、继发性腹膜炎、肺结核的早期及延长早期间治疗、强直性脊椎炎和皮肤、皮下组织感染的治疗。     

Peptide Therapeutics Versus Superbugs: Highlight on Current Research and Advancements

Antibiotics have saved several millions of lives, but its persistent use of antibiotics in the treatment of various infections, whether bacterial, fungal, viral or parasitic has lead to the development of antibiotic resistance. The rapid emergence of antibiotic resistant strains poses a serious challenge to existing antimicrobial therapies. Due to the increase in drug-resistant pathogens and failure of antibiotics the urgent need for the discovery of novel antimicrobials has been continuously emphasized in the global forum. Here we review about antimicrobial peptides (AMPs), their structural insights and recent developments. We had summarized the major classes, mechanism of action and biophysical parameters that modulate therapeutic potency of AMPs. Also, we had briefed the challenges involved in developing therapeutic peptides and the global market potential for peptide therapeutics.     

Antemortem diagnosis of an apparent case of feline candidiasis

Candidiasis in cats has always been linked with such predisposing factors as parvovirus infections and antibiotic and chemotherapeutic treatments. Moreover these cases were all diagnosed post-mortem.The clinical observations and the diagnostic procedures used in an antemortem case of probable idiopathic intestinal candidiasis in a cat are reported. The therapeutic measures used and the method of evaluating the efficacy of antimycotic treatment are also described.     

Systemic infections in multiple sclerosis and experimental autoimmune encephalomyelitis

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). It has been suggested that viral and bacterial infections contribute to the pathogenesis of MS. This review will give an overview about the influence of viral and bacterial infections on MS and experimental autoimmune encephalomyelitis (EAE). It will focus on bacterial infections and will also emphasise therapeutic consequences such as the impact of antibiotic treatment on the course of EAE. In summary, a growing body of evidence suggests that systemic infections are a risk factor for the initiation of autoimmune processes including the induction of acute events in MS. Experimental and clinical data strongly suggest early treatment of bacterial infections in MS patients to avoid aggravation and relapse.     

Fusidic acid: new opportunities with an old antibiotic.

The extensive foreign experience with fusidic acid prior to its belated introduction to Canada is reviewed. Fusidic acid is a steroid antibiotic with minimal toxic and hormonal effects that is mainly excreted through the liver. It has a predominantly bactericidal action and does not shown cross-resistance with other antibiotics. Since organisms resistant to this drug form easily in vitro when exposed to low concentrations, complementary treatment with another antibiotic may be required in some clinical situations. Although fusidic acid is active in vitro against a number of organisms, to date it has mainly been used to treat serious infections due to Staphylococcus aureus. The agent appears to be particularly valuable in the treatment of bone and joint infections and in pediatric practice. Fusidic acid will soon be available in Canada for both oral and intravenous administration. Attainable antibiotic levels in many tissues and body fluids greatly exceed the minimum inhibitory concentrations.     

Orally administered P22 phage tailspike protein reduces salmonella colonization in chickens: prospects of a novel therapy against bacterial infections

One of the major causes of morbidity and mortality in man and economically important animals is bacterial infections of the gastrointestinal (GI) tract. The emergence of difficult-to-treat infections, primarily caused by antibiotic resistant bacteria, demands for alternatives to antibiotic therapy. Currently, one of the emerging therapeutic alternatives is the use of lytic bacteriophages. In an effort to exploit the target specificity and therapeutic potential of bacteriophages, we examined the utility of bacteriophage tailspike proteins (Tsps). Among the best-characterized Tsps is that from the Podoviridae P22 bacteriophage, which recognizes the lipopolysaccharides of Salmonella enterica serovar Typhimurium. In this study, we utilized a truncated, functionally equivalent version of the P22 tailspike protein, P22sTsp, as a prototype to demonstrate the therapeutic potential of Tsps in the GI tract of chickens. Bacterial agglutination assays showed that P22sTsp was capable of agglutinating S. Typhimurium at levels similar to antibodies and incubating the Tsp with chicken GI fluids showed no proteolytic activity against the Tsp. Testing P22sTsp against the three major GI proteases showed that P22sTsp was resistant to trypsin and partially to chymotrypsin, but sensitive to pepsin. However, in formulated form for oral administration, P22sTsp was resistant to all three proteases. When administered orally to chickens, P22sTsp significantly reduced Salmonella colonization in the gut and its further penetration into internal organs. In in vitro assays, P22sTsp effectively retarded Salmonella motility, a factor implicated in bacterial colonization and invasion, suggesting that the in vivo decolonization ability of P22sTsp may, at least in part, be due to its ability to interfere with motility… Our findings show promise in terms of opening novel Tsp-based oral therapeutic approaches against bacterial infections in production animals and potentially in humans.     

Amikacin in the treatment of infectious-inflammatory diseases in patients at a therapeutic hospital

Amikacin sensitivity of 157 strains which caused infectious inflammatory diseases in patients of a therapeutic hospital was studied. It was shown that 52 and 42.9% of the isolates from patients with bronchopulmonary infections were highly and moderately sensitive to amikacin, respectively. 5 pneumococcal strains were resistant to amikacin. Among the isolates from urine of the patients with urinary infections there were no strains resistant to amikacin. Study of amikacin pharmacokinetics demonstrated expediency of antibiotic endobronchial administration to patients with bronchopulmonary diseases and aggravation of chronic purulent inflammatory processes. A favourable clinical effect of amikacin after its intramuscular or endobronchial administration was observed in 53.3% of the patients. In 30% of the patients the effect was satisfactory. In 16.7% of the patients the treatment failed. Satisfactory antibiotic tolerance in the majority of the patients was stated.     

Streptococcus pneumoniae and its bacteriophages: one long argument.

Infectious diseases currently kill more than 15 million people annually, and the WHO estimates that every year 1.6 million people die from pneumococcal diseases. Streptococcus pneumoniae (pneumococcus), a bacterium with a long biological pedigree, best illustrates the rapid evolution of antibiotic resistance, which has led to major public health concern. This article discusses the molecular basis of the two main virulence factors of pneumococcus, the capsule and cell-wall hydrolases, as well as new approaches to developing medicinal weapons for preventing pneumococcal infections. In addition, current knowledge regarding pneumococcal phages as potential contributors to virulence and the use of lytic enzymes encoded by these phages as therapeutic tools is reviewed.     

Stimulation of phagocytic processes and antibody-dependent cellular cytotoxicity of human neutrophils by cefmetazole.

Interactions between antimicrobial agents and phagocytic cells, especially neutrophils, have a potential role in the treatment of infections. The in vitro effects of cefmetazole, a novel beta-lactam antibiotic, at a therapeutic concentration reached in plasma (50 micrograms/ml) on phagocytic and cytotoxic functions of human neutrophils have been studied. In human neutrophils, adherence capacity to nylon fiber and to substrate, chemotaxis, attachment to and ingestion of Candida albicans (with serum, with decomplemented serum and without serum), ingestion of inert particles (latex beads), candidicidal activity and superoxide anion production were all stimulated by cefmetazole. Cefmetazole at this dose was a chemotactic agent for neutrophils. Antibody-dependent cellular cytotoxicity (ADCC) was also increased by this anti-microbial agent.     

Does PGE1 Vasodilator Prevent Orthopaedic Implant-Related Infection in Diabetes? Preliminary Results in a Mouse Model

Background

Implant-related infections are characterized by bacterial colonization and biofilm formation on the prosthesis. Diabetes represents one of the risk factors that increase the chances of prosthetic infections because of related severe peripheral vascular disease. Vasodilatation can be a therapeutic option to overcome diabetic vascular damages and increase the local blood supply. In this study, the effect of a PGE₁ vasodilator on the incidence of surgical infections in diabetic mice was investigated.

Methodology

A S. aureus implant-related infection was induced in femurs of diabetic mice, then differently treated with a third generation cephalosporin alone or associated with a PGE₁ vasodilator. Variations in mouse body weight were evaluated as index of animal welfare. The femurs were harvested after 28 days and underwent both qualitative and quantitative analysis as micro-CT, histological and microbiological analyses.

Results

The analysis performed in this study demonstrated the increased host response to implant-related infection in diabetic mice treated with the combination of a PGE₁ and antibiotic. In this group, restrained signs of infections were identified by micro-CT and histological analysis. On the other hand, the diabetic mice treated with the antibiotic alone showed a severe infection and inability to successfully respond to the standard antimicrobial treatment.

Conclusions

The present study revealed interesting preliminary results in the use of a drug combination of antibiotic and vasodilator to prevent implant-related Staphylococcus aureus infections in a diabetic mouse model.     

耐药菌非抗生素疗法研究进展*

抗生素耐药性是21世纪人类面临的主要公共卫生威胁之一。抗生素滥用导致越来越多的细菌产生了耐药性,使得传统抗生素治疗面临着巨大挑战。非抗生素治疗策略,如噬菌体疗法、抗菌肽疗法、抗毒力因子疗法等,在应对耐药性细菌方面具有独特的优势与临床潜力,并且能够有效避免细菌耐药性的产生与传播。综述耐药菌非抗生素疗法的研究进展,探讨其在抗感染领域的新型治疗方案。未来,耐药菌非抗生素疗法有望协同乃至替代抗生素疗法,从而应对“抗生素危机”。     

Penicillinase-producing Neisseria gonorrhoeae in Canada.

The incidence of infection with penicillinase-producing Neisseria gonorrhoeae (PPNG) reported to the Laboratory Centre for Disease Control in Ottawa has steadily increased since the first Canadian isolation of such a strain in 1976. As of September 1980 a total of 66 PPNG isolates had been referred for biological and genetic characterization as well as for central documentation of the epidemiologic aspects of each case. Over 90% of the infections were firmly traced to patients or contacts who had acquired the infection abroad; this indicates that Canada does not, as yet, have an epidemic focus of PPNG infection. This report includes a synopsis of the biological characteristics of these isolates and an analysis of the results of primary antibiotic treatment that illustrates the importance of considering spectinomycin as the antibiotic of choice for PPNG infections.