苦寒类中药抗白念珠菌的研究进展

深部真菌(主要为白念珠菌)感染现象在临床中越来越常见,真菌耐药已经成为目前治疗的主要难题.传统中医理论认为“苦寒燥湿”类中药能有效治疗各种感染,对寻找抗耐药白念珠菌新药及协同药物具有一定的指导意义.该文主要总结阐述苦寒类中药抗真菌研究进展.     

Effectiveness of the antibiotics chloramphenicol and rifampin in the treatment of Streptococcus pneumoniae-induced meningitis and systemic infections

Streptococcus pneumoniae, a common pathogen in pediatric infections, has become resistant to penicillin and make these infections difficult to treat. Rifampin and chloramphenicol have been recommended as alternative therapies, since they are less costly and more accessible to communities with limited resources. However, their use may be restricted by the differing levels of resistance found in target populations. The objective was to determine minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) for chloramphenicol and rifampin in strains of S. pneumoniae. These strains were newly isolated from children under age 5 that had demonstrated systemic infections and meningitis. A subgroup of 107 isolates of S. pneumoniae was selected from 324 strains isolated during a period of 2 years (1994-1996). Among these isolates, 60 were penicillin-resistant and 47 were susceptible; 53 isolates were from children with meningitis. MIC and MBC for chloramphenicol and rifampicin were obtained by standard methods recommended by the National Committee for Clinical Laboratory Standards (NCCLS). S. pneumoniae ATCC strain 49619 served as the control. An isolate was considered susceptible to chloramphenicol when MIC = 4 microg/ml and resistant when MIC = 8 microg/ml. A strain was considered susceptible to rifampin when MIC = 1 microg/ml and resistant when MIC = 4 microg/ml. MBC was determined by recording the lower concentration of the antibiotic that inhibited 99.9% of the initial inoculum. Chloramphenicol resistance was found in 21% of the 107 isolates. In the group susceptible to penicillin, 11% were resistant to chloramphenicol and in the group resistant to penicillin 28% was resistant to chloramphenicol as well. MBC was found > 4 microg/ml in 28% of the isolates susceptible to penicillin and in 60% of the resistant isolates. No isolates were found resistant to rifampin. However, 2 penicillin resistant isolates showed CBM > 1 microg/ml to rifampin, and one with CIM = 1 microg/ml had a MBC to rifampicin of 16 microg/ml. Meningitis isolates showed higher CIM and CBM than the group of total isolates. These data suggest that chloramphenicol is not recommended for invasive infections caused by S. pneumoniae in Colombia. Rifampin is a more effective therapy in combination with other antibiotics for treatment of this kind of infections. Further studies are necessary to clarify the significance of low levels of MBC to rifampin found in some strains, since this may affect the efficacy of therapies that include this antibiotic.     

Resistance to anticoccidial drugs in fowl

Resistance has been encountered wherever drugs have been used extensively for the control of parasitic infections. The poultry industry is dependent upon drugs for the control of coccidiosis, a major disease of chickens caused by protozoan parasites of the genus Eimeria. In modern poultry production, drugs are used prophylactically for the prevention of coccidiosis by including them in the diet. This has inevitably led to the development of resistance. We have been fortunate in that new drugs have become available to replace those to which resistance has developed, but this situation is unlikely to continue. The problem of drug resistance, discussed here by David Chapman, has provided impetus for the development of new approaches (such as vaccination) for the control of coccidiosis.     

Rapid Response to Selection,Competitive Release and Increased Transmission Potential of Artesunate-Selected Plasmodium chabaudi Malaria Parasites

The evolution of drug resistance, a key challenge for our ability to treat and control infections, depends on two processes: de-novo resistance mutations, and the selection for and spread of resistant mutants within a population. Understanding the factors influencing the rates of these two processes is essential for maximizing the useful lifespan of drugs and, therefore, effective disease control. For malaria parasites, artemisinin-based drugs are the frontline weapons in the fight against disease, but reports from the field of slower parasite clearance rates during drug treatment are generating concern that the useful lifespan of these drugs may be limited. Whether slower clearance rates represent true resistance, and how this provides a selective advantage for parasites is uncertain. Here, we show that Plasmodium chabaudi malaria parasites selected for resistance to artesunate (an artemisinin derivative) through a step-wise increase in drug dose evolved slower clearance rates extremely rapidly. In single infections, these slower clearance rates, similar to those seen in the field, provided fitness advantages to the parasite through increased overall density, recrudescence after treatment and increased transmission potential. In mixed infections, removal of susceptible parasites by drug treatment led to substantial increases in the densities and transmission potential of resistant parasites (competitive release). Our results demonstrate the double-edged sword for resistance management: in our initial selection experiments, no parasites survived aggressive chemotherapy, but after selection, the fitness advantage for resistant parasites was greatest at high drug doses. Aggressive treatment of mixed infections resulted in resistant parasites dominating the pool of gametocytes, without providing additional health benefits to hosts. Slower clearance rates can evolve rapidly and can provide a strong fitness advantage during drug treatment in both single and mixed strain infections.     

Redesign of glycopeptide antibiotics: back to the future

The glycopeptide antibiotics are the most important class of drugs used in the treatment of resistant bacterial infections including those caused by methicillin-resistant Staphylococcus aureus (MRSA). After more than 50 years of clinical use, the emergence of glycopeptide-resistant Gram-positive pathogens such as vancomycin-resistant enterococci (VRE) and vancomycin-resistant Staphylococcus aureus (VRSA) presents a serious global challenge to public health at a time few new antibiotics are being developed. This has led to renewed interest in the search for additional effective treatments including the development of new derivatives of the glycopeptide antibiotics. General approaches have been explored for modifying glycopeptide antibiotics, typically through the derivatization of the natural products themselves or more recently through chemical total synthesis. In this Perspective, we consider recent efforts to redesign glycopeptide antibiotics for the treatment of resistant microbial infections, including VRE and VRSA, and examine their future potential for providing an even more powerful class of antibiotics that are even less prone to bacterial resistance.     

Specific and Selective Bacteriophages in the Fight against Multidrug-resistant Acinetobacter baumannii

Acinetobacter baumannii causes serious infections especially in immunocompromised and/or hospitalized patients. Several A. baumannii strains are multidrug resistant and infect wounds, bones, and the respiratory tract. Current studies are focused on finding new effective agents against A. baumannii. Phage therapy is a promising means to fight this bacterium and many studies on procuring and applying new phages against A. baumannii are currently being conducted. As shown in animal models, phages against multidrug-resistant A. baumannii may control bacterial infections caused by this pathogen and may be a real hope to solve this dangerous health problem.     

The Chemotherapy of Protozoal Infections of Veterinary Importance1

The use of drugs in domestic animals is dominated by considerations of cost-effectiveness and profitability. They are extensively used against coccidial infections of poultry where they are an important factor in intensive husbandry. Ionophore antibiotics, which dominate this field, may have applications in ruminants. Imidocarb is of therapeutic and prophylactic value against babesial infections and there are new prospects for control of theileriasis. Effective drugs for the control of African trypanosomiasis are limited and attention is being given to alternative uses of available compounds.     

Anti-tuberculosis drug resistance and therapeutic dead end

The irrational use of antituberculous drugs led to the emergence of resistant strains of M. tuberculosis. Every year in the world, around 440 000 new tuberculosis cases are due to bacilli that are resistant to the two main antituberculous drugs, isoniazid and rifampicin (also known as multidrug resistant or MDR). Treatment of MDR tuberculosis is difficult and has been based for twenty years on the use of fluoroquinolones and injectable antibiotics such as amikacin, kanamycin and capreomycin. Consequently, strains resistant to the latter drugs, so-called extensively drug resistant strains or XDR, have recently emerged. XDR tuberculosis is very difficult to treat and the prognosis is very close to that of untreated tuberculosis with a mortality rate that can reach 50 % to 100 %. To avoid the emergence of more resistant strains that may lead to almost untreatable disease, we must focus our efforts on the right management of drug susceptible tuberculosis. Basic principles for avoiding accumulation of resistances in selected strains are outlined in the article.     

Increase in drug resistance among Shigella dysenteriae,Sh flexneri,and Sh boydii.

Two thousand three hundred and seventy strains of Shigella dysenteriae, Sh flexneri, and Sh boydii isolated in England and Wales from 1974 to 1978 were tested for resistance to 12 antimicrobial drugs. Eighty per cent of strains were resistant to one or more drugs, with sulphonamide resistance occurring most frequently. Resistance to streptomycin, tetracycline, ampicillin, and chloramphenicol increased during the period, as did the incidence of multiple resistance. Most infections due to Sh dysenteriae, Sh flexneri, and Sh boydii are acquired abroad, and the increasing incidence of drug resistance among these organisms contrasts with the decreasing incidence of resistance among the indigenous Sh sonnei. These findings may indicate the need for better control of antibiotic use, particularly in developing countries.     

Trends and challenges in the effective and sustainable control of Haemonchus contortus infection in sheep. Review

Haemonchosis, with its very wide distribution, has become a very important production constraint in sheep farms in tropical, subtropical and temperate regions worldwide. Various intrinsic and extrinsic factors determine the survival of Haemonchus contortus and hence the development of the disease in the animal. In general, control of gastrointestinal nematode infestation in sheep relies heavily on anthelmintic treatments. However, the indiscriminate use of these drugs has led to the widespread emergence of drug resistant strains of parasites, that has necessitated the development and use of various parasite control methods such as grazing management, biological agents and vaccines and the selection of resistant breeds of animals, with or without moderate use of anthelmintics. The ultimate goal of such control programs is to enhance productivity, while minimising risks regarding drug resistance and consumer and environmental concerns. This review attempts to highlight the different methods employed in the control of haemonchosis in sheep and the practical limitations associated with both control programs and the internal and external factors associated with the parasite and its microenvironment.     

Microbiologic consequences of new approaches to managing hematologic malignancies

Opportunistic infections have always been pitfalls on the road of progress in the treatment of diseases that are accompanied by compromised host defences. Because of the severe morbidity and mortality associated with these infections, they have become substantial challenges for the clinicians who offer such patients care. With medical progress, the number of immunocompromised patients is still steadily climbing and it has become evident that deficiencies in host defences mechanisms are multiple as well as changing in harmony with alterations in treatment modalities for underlying diseases. Under normal circumstances, the intact epithelial surfaces of the gastrointestinal tract will prohibit invasion by micro-organisms and the mucociliary barrier of the respiratory tract prevents aspiration of fungal cells and spores, while, in contrast, dead or damaged tissue creates a nidus for infection. It is, however, questionable whether transmigration of organisms inevitably leads to infection. With the growing use of potent immunosuppressive purine analogues, fludarabine, pentostatin and cladibrine, and anti-T and anti-B cell antibodies, such as rituximab and campath, in the management of lymphoreticular malignancies, in combination with increasing emphasis on dose intensity, the number of patients at risk has almost reached levels encountered in recipients of allogenic stem cell grafts as a consequence of long-lasting deficiencies in the cellular immunity. The spectrum of opportunistic pathogens are shifting as anti-leukemic and anti-lymphoma therapy become more intensive and bone marrow transplant practices evolve. Recent studies demonstrate, that patients treated with nonmyeloablative allogeneic transplantation (or "minitransplants") to reduce transplant-related toxicity, are at high risk of contracting a serious infections. Initially bacterial infections were most problematic. However, as strategies to control bacterial infections improved, viruses demanded more attention from the clinicians but the associated morbidity declined due to advances in rapid diagnostics and the introduction of effective antivirals such as acyclovir and ganciclovir. Next to viruses, resistant bacteria, particularly Gram-positive organisms like enterococci and methicillin-resistant staphylococci urged to vigilance. It was obvious that enhanced use of antibacterials inevitably will be accompanied by selection and induction of resistant organisms. Today, opportunistic fungi have become the most frequent and dangerous pathogens. Since the 1980's the rate of nosocomial invasive fungal diseases has doubled without any sign of slowing at the turn of the millenium. During the past decades we have even observed an increased incidence of invasive fungal infections in patients who are not in an end stage of their underlying disease. Yeasts and moulds rank amongst the most frequently isolated pathogens. The relative incidence of the various fungal infections depends on geography as well as on medical practices and local conditions. Candida Aspergillus species remain the prominent fungal pathogens but more rare species are increasingly cultured.     

Inhibition of Candida albicans growth by brominated furanones

Candida albicans is the most virulent Candida species of medical importance, which presents a great threat to immunocompromised individuals such as HIV patients. Currently, there are only four classes of antifungal agents available for treating fungal infections: azoles, polyenes, pyrimidines, and echinocandins. The fast spread of multidrug resistant C. albicans strains has increased the demand for new antifungal drugs. In this study, we demonstrate the antifungal activity of brominated furanones on C. albicans. Studying the structure and activity of this class of furanones reveals that the exocyclic vinyl bromide conjugated with the carbonyl group is the most important structural element for fungal inhibition. Furthermore, gene expression analysis using DNA microarrays showed that 3 μg/mL of 4-bromo-5Z-(bromomethylene)-3-butylfuran-2-one (BF1) upregulated 32 C. albicans genes with functions of stress response, NADPH dehydrogenation, and small-molecule transport, and repressed 21 genes involved mainly in cell-wall maintenance. Interestingly, only a small overlap is observed between the gene expression changes caused by the representative brominated furanone (BF1) in this study and other antifungal drugs reported in literature. This result suggests that brominated furanones and other antifungal drugs may target different fungal proteins or genes. The existence of such new targets provides an opportunity for developing new agents to control fungal pathogens which are resistant to currently available drugs.     

The current status of drug resistance in malaria

Drug resistant malaria is a major health problem; it poses a threat to the lives of millions of people and renders it less possible for the worldwide eradication programme to attain its goal in the foreseeable future. At present Plasmodium falciparum is resistant to varying degrees to all antimalarial drugs available e.g. chloroquine, sulfadoxine and pyrimethamine, quinine and even to the new compound, mefloquine.Chloroquine-resistant P. falciparum originated in Thailand some 25 years ago has spread in all directions to Southeast Asia, Western Pacific, to central and southeast India, East Africa and West Africa. In South America, it started in Colombia and now affects the whole of Central and South America with the exception of Argentina, Paraguay and Peru which practically have no falciparum malaria.The mechanism of drug resistance in malaria parasites is believed to be due to gene mutation selected under drug pressure. It may be one-step as in pyrimethamine or multi-step as in chloroquine. Resistant mutation occurs both in schizogony and sporogony. The parasites lose their S strains through hybridization or overgrowth, shifting in character progressively towards high grade resistance.Policies that may help to minimise further development of resistance to existing compounds and to safeguard any new drugs that may be developed in the future include (1) limit the distribution of antimalarials; (2) select priority groups for prophylaxis; (3) use the gametocidal drug primaquine to restrict transmission of resistant strains; (4) establish an effective drug monitoring system; (5) only deploy drugs for control as part of an integrated campaign; (6) control use of new antimalarial; (7) encourage the use of tested effective drug regimens for treatment and (8) encourage research on antimalarials.     

Comparative proteomics to evaluate multi drug resistance in Escherichia coli

Drug resistance in food-borne bacterial pathogens is an almost inevitable consequence of the use of antimicrobial drugs, used either therapeutically or to avoid infections in food-producing animals. In the past decades, the spread and inappropriate use of antibiotics have caused a considerable increase of antibiotics to which bacteria have developed resistance and, moreover, bacteria are becoming resistant to more than one antibiotic simultaneously. Understanding mechanisms at the molecular level is extremely important to control multi-resistant strains and to develop new therapeutic strategies. In the present study, comparative proteomics was applied to characterize membrane and cytosolic proteome in order to investigate the regulation of protein expression in multi-resistance E. coli isolated from young never vaccinated water buffalo. Results highlighted differentially expressed proteins under multi drug resistance conditions giving new insights about mechanisms involved in resistance, as quorum sensing mechanisms, and suggesting possible novel bacterial targets to develop alternative antibiotic drugs.     

Resistance of Haemophilus influenzae to Trimethoprim

Out of 210 isolates of Haemophilus influenzae obtained from the sputum of 63 patients with chronic respiratory infections 109 (52%) were resistant to trimethoprim-sulphamethoxazole by the disc test. The minimal inhibitory concentrations of trimethoprim for 17 out of 18 strains recorded as resistant were 10 μg/ml or higher. Resistant strains were isolated from time to time from 32 (82%) out of 39 patients known to have been treated with trimethoprim-sulphamethoxazole, compared with only 1 (12·5%) out of 8 patients known not to have been treated with this drug combination. Resistant strains were isolated most frequently from patients who had received long-term treatment. Since sulphamethoxazole penetrates from the blood into the bronchial secretions less readily than does trimethoprim it seems likely that the ratio of the two drugs in the bronchial tree is far from ideal. This may be an important factor in the use of these drugs for chest infections.     

Control of the sheep blowfly in Australia and New Zealand – are we there yet?

The last 50 years of research into infections in Australia and New Zealand caused by larvae of the sheep blowfly, Lucilia cuprina, have significantly advanced our understanding of this blowfly and its primary host, the sheep. However, apart from some highly effective drugs it could be argued that no new control methodologies have resulted. This review addresses the major areas of sheep blowfly research over this period describing the significant outcomes and analyses, and what is still required to produce new commercial control technologies. The use of drugs against this fly species has been very successful but resistance has developed to almost all current compounds. Integrated pest management is becoming basic to control, especially in the absence of mulesing, and has clearly benefited from computer-aided technologies. Biological control has more challenges but natural and perhaps transformed biopesticides offer possibilities for the future. Experimental vaccines have been developed but require further analysis of antigens and formulations to boost protection. Genetic technologies may provide potential for long-term control through more rapid indirect selection of sheep less prone to flystrike. Finally in the future, genetic analysis of the fly may allow suppression and perhaps eradication of blowfly populations or identification of new and more viable targets for drug and vaccine intervention. Clearly all these areas of research offer potential new controls but commercial development is perhaps inhibited by the success of current chemical insecticides and certainly requires a significant additional injection of resources.     

Multicellular organization in bacteria as a target for drug therapy

Antibiotic treatments are now reaching the limit of their efficiency, especially in hospitals where certain bacteria are resistant to all available drugs. The development of new drugs against which resistance would be slower to evolve is an important challenge. Recent advances have shown that a potential strategy is to target global properties of infections instead of harming each individual bacterium. Consider an analogy with multicellular organisms. In order to kill an animal two strategies are possible. One can kill each of its cells individually. This is what antibiotics do to get rid of bacterial infections. An alternate way, for instance, is to disorganize the hormonal system of animal's body, leading eventually to its death. This second strategy could also be employed against infections, in place of antibiotics. Bacteria are indeed often involved into coordinated activities within a group, and certain drugs are able to disorganize these activities by blocking bacterial communication. In other words, these drugs are able to target infections as a whole, rather than individuals within infections. The present paper aims at analysing the consequence of this peculiarity on the evolution of bacterial resistance. We use a mathematical model, based on branching process, to calculate the fixation probability of a mutant resistant to this type of drug, and finally to predict the speed of resistance evolution. We show that this evolution is several orders of magnitude slower than in the case of antibiotic resistance. The explanation is as follows. By targeting treatments against adaptive properties of groups instead of individuals, we shift one level up the relevant unit of organization generating resistance. Instead of facing billions of bacteria with a very rapid evolutionary rate, these alternate treatments face a reduced number of larger organisms with lower evolutionary potential. In conclusion, this result leads us to emphasize the strong potential of anti‐bacterial treatments aiming at disorganizing social traits of microbes rather than at killing every individual.     

Triclabendazole: new skills to unravel an old(ish) enigma

Triclabendazole was introduced in the early 1980s for the treatment of Fasciola hepatica infections in livestock. Due to its high activity against immature flukes, it has become established as the principal anti-fluke drug on the market. More recently, triclabendazole has been used to treat human cases of fascioliasis and is now the drug of choice for this infection, too. Resistance to triclabendazole was first reported in 1995 in a field population in Australia and, since that time, resistant populations have been identified in several countries in Europe. Parallel to the spread of resistance has been a sharp increase in the prevalence of fascioliasis, which has been attributed largely to climate changes. Consequently, farmers are faced with an alarming scenario, as none of the other fasciolicides on the market possess such high activity against the damaging immature stages of fluke. The main aim of this review is to assess current understanding of the mechanism of action of triclabendazole against the fluke and the mechanism by which the fluke has become resistant to it. The use of triclabendazole against animal and human infections is summarized and suggestions are given on ways to deal with resistance. Gaps in the knowledge of various aspects of its use are highlighted and this may serve to open up future research areas.     

Progress in the prevention and control of schistosomiasis and soil-transmitted helminthiasis

In the last two decades important progress has been made in the understanding the epidemiology and the disease burden of schistosomiasis and soil-transmitted nematodes infection. In addition, practical tools for disease control have been developed and a strategy for the prevention and control of morbidy of schistosomaisis and soil-transmitted nematodes infection has been endorsed by the World Health Organization. This paper presents the recent progress in the prevention and control of these infections: the estimates of chronic and subtle morbidity in high risk groups and the evidence that these chronic and severe sequelae of infections can be reversed by appropriate treatment; the use of anthelminthic drugs during pregnancy and lactation; the relevance to control morbidity due to these infections also in pre-school children; the efficacy of anthelminthic drugs and the possible threat of drug resistance; price, quality and accessibility of treatment by delivering drugs through the school system and ways of reaching also non-enrolled school-age children. Finally, the strategy, targets and recommendations of the World Health Organization for the control of schistosomiasis and soil-transmitted nematodes infection are described.