牙周局部缓释药物治疗牙周炎的研究进展

目的：对牙周局部缓释抗菌药物治疗牙周炎的最新进展作一综述。方法：从常用抗菌药物、缓释材料和市场产品进展三大方面对药物的作用机制和临床治疗效果进行综述。结果：与全身给药相比,牙周局部缓释抗菌药物辅助治疗牙周炎可以使牙周袋内有较高的药物浓度并且维持较长时间,该治疗方法毒副作用小、靶向性好。并且缓释材料对能否成功的研制一种理想的缓释制剂来说至关重要。结论：随着抗菌药物和缓释材料的发展和应用,将会有更多安全、有效、稳定性好的新型牙周局部缓释产品上市,以应用于牙周炎治疗中。     

Interactions between oral contraceptives and antifungals/antibacterials. Is contraceptive failure the result?

The effectiveness of oral contraceptives may be impaired by concomitant treatment with antimicrobials. This may occur because of reductions in plasma concentrations of ethinylestradiol by the induction of hepatic metabolism, as for rifampicin (rifampin) and possibly griseofulvin, or in a small percentage of women because of interference with enterohepatic recirculation. There are no scientific data to support the anecdotal evidence that the concomitant use of combined oral contraceptives and antimicrobials reduces contraceptive efficacy in the majority of women. It has been postulated that there is a subset of women in whom the enterohepatic recirculation of ethinylestradiol plays an important role. In these women the action of an antimicrobial may reduce the efficacy of oral contraceptives by interfering with this mechanism. Studies that have quantitatively examined these effects may have failed to include women from this subset because of the small numbers involved in the studies. On the other hand, there are no good prospective studies comparing contraceptive failure rates between compliant women who use combined oral contraceptives with and without antimicrobials. All women using combined oral contraceptives should be informed of the very low level of risk of interactions with antimicrobials (probably about 1%) and that it is not possible to identify who may be at risk. Women concerned about this low level of risk should be given information about the use of barrier methods or avoidance of intercourse during the first 7 days of concomitant antimicrobial therapy and for 7 subsequent days. Women who have had previous contraceptive failures or developed breakthrough bleeding during concomitant antimicrobial use should be strongly advised to follow these precautions, as they may be part of the subset of women at higher risk of contraceptive failure.     

Antimicrobial drug delivery to the eye

A major obstacle in the treatment of ocular infections is the difficulty in obtaining adequate antimicrobial drug concentration at the site of infection. This article reviews the pharmacokinetic principles of ophthalmic drug delivery as it pertains to antimicrobial therapy. The administration of antimicrobials by topical application, subconjunctival injection, intravitreal injection, vitreous replacement fluid, and systemic administration are addressed. Representative data on the intraocular penetration of antimicrobials as well as recommended doses of drugs for ocular infections are presented.     

Effect of chitosan on a periodontal pathogen Porphyromonas gingivalis

Local delivery systems of antimicrobial agents for treatment of the periodontal diseases received considerable attention during the past decade due to the disadvantages of the systemic administration. An ideal formulation should exhibit ease of delivery, a good retention at the application site, and a controlled release of the drug. The application of bioadhesive gels provides a long stay in the oral cavity, adequate drug penetration, high efficacy and acceptability. In dentistry and oral medicine, various applications of chitosan, which is a bioadhesive polymer have been proposed due to its favorable properties such as biocompatibility and biodegradability. The aim of this study was to determine the antimicrobial activity of chitosan formulations either in gel or film form against a periodontal pathogen, Porphyromonas gingivalis. The viscosity, bioadhesive properties and antimicrobial activity of chitosans at different molecular weight and deacetylation degree were evaluated in the absence or presence of chlorhexidine gluconate (Chx), incorporated into the formulations at 0.1 and 0.2% concentrations. The flow property of the gels were found to be suitable for topical application on the oral mucosa and to syringe into the periodontal pocket. Bioadhesion of the gels and films examined ex-vivo using fresh porcine buccal mucosa showed that both the film and gel formulations exert bioadhesive properties and was not affected by incorporation of Chx. Chitosan is shown to have an antimicrobial activity against P. gingivalis and this was higher with high molecular weight chitosan. The combination of chitosan with Chx showed a higher activity when compared to that of Chx alone, which would provide Chx application at lower concentrations thus avoiding its unwanted side effects. Chitosan films and gels seem to be promising delivery systems for local therapy of periodontal diseases with its bioadhesive property and antimicrobial activity.     

Hospital pharmacy acquisition of nonstocked antimicrobials—current processes and areas for improvement

BackgroundThe delivery of prompt and appropriate antimicrobial therapy for life-threatening infections is an important antimicrobial stewardship measure and a priority for hospitals.ObjectivesTo better understand U.S. hospital pharmacy stocking processes and acquisition of nonstocked antimicrobials and to identify strategies for improving this process.MethodsThis mixed-methods study recruited infectious diseases and antimicrobial stewardship pharmacists. Semistructured interviews with pharmacists in Minnesota were conducted via video conferencing software from January 21, 2021, to March 17, 2021. Audio recordings of the interviews guided survey development and were also transcribed, coded, and qualitatively analyzed. Surveys were distributed throughout the United States via an e-mail listserv, and responses were collected between August 5, 2021, and September 15, 2021.ResultsTen interviews and 78 surveys were included in the analysis. Formulary and stocking practices varied based on institution. Stocking decisions were most frequently based on the frequency of use, clinical utility, and cost of antimicrobials. Nonstocked antimicrobials were often ordered from the wholesale distributor but, if needed urgently, acquired from another local institution. Antibacterial agents were the most frequently needed nonstocked antimicrobials, especially those targeting multidrug-resistant gram-negative bacteria. When acquiring nonstocked antimicrobials, barriers include process inefficiencies, cost, availability, and safety concerns. Improved information sharing between local institutions may help improve this process.ConclusionIn this exploratory study, antimicrobial stocking practices varied within U.S. hospitals. Acquisition of nonstocked, urgently needed antimicrobials from neighboring hospitals may be common; however, this process lacks guidance and is often inefficient. Establishing better mechanisms for information sharing may improve this process and should be explored.     

The use of cephalosporins for gonorrhea: the impending problem of resistance

Gonorrhea remains an important clinical and public health problem throughout the world. Gonococcal infections have historically been diagnosed by Gram stain and culture but are increasingly diagnosed through nucleic acid tests, thereby eliminating the opportunity for antimicrobial susceptibility testing. Gonococcal infections are typically treated with single-dose therapy with an agent found to cure > 95% of cases. Unfortunately, the gonococcus has repeatedly developed resistance to antimicrobials including sulfonamides, penicillin, tetracyclines and fluoroquinolones. This has now left third-generation cephalosporins as the lone class of antimicrobials recommended as first-line therapy for gonorrhea in some regions. However, resistance to oral third-generation cephalosporins has emerged and spread in Asia, Australia and elsewhere. The mechanism of this resistance seems to be associated with a mosaic penicillin binding protein (penA) in addition to other chromosomal mutations previously found to confer resistance to β-lactam antimicrobials (ponA, mtrR, penB, pilQ). Few good options exist or are in development for treating cephalosporin-resistant isolates, as most have had multidrug resistance. Preventing the spread of resistant isolates will depend on ambitious antimicrobial management programs, strengthening and expanding surveillance networks, and through effective sexually transmitted disease control and prevention.     

Antimicrobial activity of cefetamet against clinically isolated microbial strains collected from urban RTI patients]

The authors studied antimicrobial activities of cefetamet (CFMT) and other leading oral antimicrobials of beta-lactam class against clinically isolated strains from urban respiratory tract infection (RTI) patients from January to March, 1992. 1. CFMT showed potent antimicrobial activities against "3 primary pathogens" of RTIs i.e., Streptococcus pyogenes, Streptococcus pneumoniae, and Haemophilus influenzae, but the drug had a slightly higher MIC than those of a few oxime-type cephems already on the market. 2. CFMT was as stable as cefixime to beta-lactamase, generated by Moraxella subgenus Branhamella catarrhalis, which reduces the antimicrobial activity of cephems. 3. Blood concentrations of CFMT after administering cefetamet pivoxil (CFMT-PI), an oral form of the drug, exceeded the MIC80 against the "3 primary pathogens" as well as M. (B) catarrhalis and Klebsiella pneumoniae, for a duration of approximately 9 and 11 hours, respectively, after single doses of 250 and 500 mg. This suggests that CFMT could remain above the MICs for a sufficient time period with twice daily dosages of normal dose levels. 4. It is concluded that CFMT-PI will be useful for treating urban RTIs.     

Nanoparticles and the control of oral infections

The potential of antimicrobial nanoparticles to control oral infections is reviewed. Such particles can be classified as having a size no greater than 100 nm and are produced using traditional or more novel techniques. Exploitation of the toxic properties of nanoparticles to bacteria, fungi and viruses, in particular metals and metal oxides, as well as their incorporation into polymeric materials have increased markedly over the past decade. The potential of nanoparticles to control the formation of biofilms within the oral cavity, as a function of their biocidal, anti-adhesive and delivery capabilities, is now receiving close attention. Latest insights into the application of nanoparticles within this field, including their use in photodynamic therapy, will be reviewed. Possible approaches to alter biocompatibility and desired function will also be covered.     

临床药师在抗菌药物管理中的作用探讨

本文通过介绍国外抗菌药物的管理程序与感染专业临床药师的工作模式,结合我国临床药师的工作现状,探讨临床药师在抗菌药物管理中的作用.主要内容为美国和英国药师在限制使用药品管理中的作用、我国临床药师参与卫生部抗菌药物临床应用监测网、参与医院抗菌药物品种的评估和基本用药目录的制定、参与处方点评与抗菌药物的主动干预等情况.通过与国外药师工作的比较,认为感染专业临床药师应该在感染性疾病的病房里有自己的工作岗位,不断培训,并通过处方点评和有可监督抗菌药物使用情况的网络系统,在一定程度上直接参与抗菌药物合理应用的干预工作.并提出参与抗菌药物的管理计划,减少药物的不合理使用,优化抗菌药物治疗,同时降低药物带来的不良后果是感染专业临床药师工作的目的和发展方向.     

Therapeutic advances of new fluoroquinolones

Fluoroquinolone antimicrobials have been available for over 10 years. Recent modifications to nuclear side-chains have enhanced both the antimicrobial and pharmacokinetic profiles of this class. Rapidly increasing antimicrobial resistance among community and hospital bacterial pathogens has diminished therapeutic options. Infections caused by such pathogens, including drug-resistant Streptococcus pneumoniae and multi-resistant Enterobacteriaceae are now treatable by few classes of antibacterials, one of these being the fluoroquinolones. Ciprofloxacin was one of the first effective agents available in both iv. and oral formulations for the treatment of Gram-negative infection, resistant to other antibiotics. More recent developments, such as sparfloxacin and grepafloxacin, are more effective in vitro against Gram-positive pathogens, although their safety profile may be less promising. Fluoroquinolones not yet in widespread clinical use, including trovafloxacin, clinafloxacin and moxifloxacin, hold considerable promise as community ‘respiratory antimicrobials’ and the results of clinical trials are awaited with anticipation. In this review, the three generations of fluoroquinolone development are examined and the relative antimicrobial, pharmacokinetic, clinical and safety profiles of available and developmental quinolones are compared.     

Selecting antibacterials for outpatient parenteral antimicrobial therapy : pharmacokinetic-pharmacodynamic considerations

Some infectious diseases require management with parenteral therapy, although the patient may not need hospitalisation. Consequently, the administration of intravenous antimicrobials in a home or infusion clinic setting has now become commonplace. Outpatient parenteral antimicrobial therapy (OPAT) is considered safe, therapeutically effective and economical. A broad range of infections can be successfully managed with OPAT, although this form of treatment is unnecessary when oral therapy can be used. Many antimicrobials can be employed for OPAT and the choice of agent(s) and regimen should be based upon sound clinical and microbiological evidence. Assessments of cost and convenience should be made subsequent to these primary treatment outcome determinants. When designing an OPAT treatment regimen, the pharmacokinetic and pharmacodynamic characteristics of the individual agents should also be considered. Pharmacokinetics (PK) is the study of the time course of absorption, distribution, metabolism and elimination of drugs (what the body does to the drug). Clinical pharmacokinetic monitoring has been used to overcome the pharmacokinetic variability of antimicrobials and enable individualised dosing regimens that attain desirable antimicrobial serum concentrations. Pharmacodynamics (PD) is the study of the relationship between the serum concentration of a drug and the clinical response observed in a patient (what the drug does to the body). By combining pharmacokinetic properties (peak [C(max)] or trough [C(min)] serum concentrations, half-life, area under the curve) and pharmacodynamic properties (susceptibility results, minimum inhibitory concentrations [MIC] or minimum bactericidal concentrations [MBC], bactericidal or bacteriostatic killing, post-antibiotic effects), unique PK/PD parameters or indices (t > MIC, C(max)/MIC, AUC(24)/MIC) can be defined. Depending on the killing characteristics of a given class of antimicrobials (concentration-dependent or time-dependent), specific PK/PD parameters may predict in vitro bacterial eradication rates and correlate with in vivo microbiologic and clinical cures. An understanding of these principles will enable the clinician to vary dosing schemes and design individualised dosing regimens to achieve optimal PK/PD parameters and potentially improve patient outcomes. This paper will review basic principles of useful PK/PD parameters for various classes of antimicrobials as they may relate to OPAT. In summary, OPAT has become an important treatment option for the management of infectious diseases in the community setting. To optimise treatment course outcomes, pharmacokinetic and pharmacodynamic properties of the individual agents should be carefully considered when designing OPAT treatment regimens.     

Clinical and economic effect of ciprofloxacin as an alternative to injectable antimicrobial therapy

The effect of the use of oral ciprofloxacin on patient outcome and the cost of antimicrobial therapy was investigated. In 1988 ciprofloxacin was placed on the antimicrobial formulary at a Veterans Affairs medical center. Patients with urinary tract infections, soft tissue infections, osteomyelitis, or pneumonia due to organisms that were documented as being susceptible to ciprofloxacin and either resistant to other oral antimicrobials or susceptible to other oral antimicrobials in patients allergic to such agents were monitored in a prospective open study over 12 months. When a patient was enrolled, the physician was asked to select the i.v. antimicrobial regimen that would have been used if ciprofloxacin were not available. Patient outcome was determined from medical records, and the difference in the costs of the oral and i.v. regimens was calculated. Clinical cure occurred in 96/100 (96%) of patients with urinary tract infection, 19/22 (86%) with soft tissue infection, 14/16 (88%) with osteomyelitis, and 10/12 (83%) with pneumonia. The overall cure rate was 139/150 (93%). The 11 clinical failures occurred in patients infected with methicillin-resistant Staphylococcus aureus (MRSA) alone, group D enterococcus alone, MRSA and Pseudomonas sp., and Pseudomonas sp. alone. The total cost avoidance achieved by using oral ciprofloxacin instead of i.v. antimicrobials was $77,158. Oral ciprofloxacin was an effective and cost-efficient alternative to traditional i.v. antimicrobial therapy in the patients studied.     

Implementing a pharmacist-led sequential antimicrobial therapy strategy: a controlled before-and-after study

Sequential antimicrobial therapy is an important part of antimicrobial stewardship and intends to improve the timeliness of switch to oral antimicrobials. The aim of this study was to assess the impact of the introduction of guidelines and criteria for switching to oral antimicrobials. Setting The study was conducted in a 753-bed academic hospital in Ireland. Methods The study was prospective and of controlled before and after design. Patients admitted under the care of a medical consultant were screened for inclusion. The study was divided into pre-intervention and post-intervention phases. Patients admitted and prescribed IV antimicrobials were enrolled into either a study group or control group. Post-intervention, the intervention to the study group consisted of application of stickers and criteria for switch to oral antimicrobial therapy to the drug chart. Pre-intervention in the study group and in both phases in the control group, conventional practice of clinical pharmacists reviewing drug charts and contacting prescribers to discuss a switch to an oral antimicrobial continued. The duration of intravenous treatment, the timeliness of switch to oral therapy, length of stay and cost savings were measured. Main outcome measure The duration of intravenous antimicrobial therapy in the pre-intervention and post-intervention phases in both study and control groups. Results Pre-intervention, 85 courses of IV antimicrobials were prescribed to study group patients, compared to 60 in the control group. Post-intervention, there were 92 courses in the study group and 53 in the control group. The duration of IV antimicrobial treatment reduced significantly in the study group post-intervention, compared to the control group (P = 0.02). The timeliness of the switch also improved significantly in the study group post-intervention (P = 0.017). No improvement occurred in the control group. The median length of stay was not reduced post-intervention. Antimicrobial costs reduced by a mean of ?6.41 in the study group post-intervention. Conclusion This controlled before and after study demonstrates successful implementation of a pharmacist-led antimicrobial stewardship strategy. Duration of IV antimicrobial treatment reduced significantly and the timeliness of switch significantly improved. This study may be used as a template for the introduction of further pharmacist-led antimicrobial stewardship initiatives.     

Implications on Emergence of Antimicrobial Resistance as a Critical Aspect in the Design of Oral Sustained Release Delivery Systems of Antimicrobials

Purpose To assess the effects of the unabsorbed fraction of an orally administered antimicrobial drug which enters the colon on the emergence of resistance among the natural microflora, a phenomenon largely overlooked so far despite its clinical importance, especially when sustained release formulations are used. Methods Effects of an orally administered model β-lactam antibiotic (amoxicillin) on emergence of resistant bacteria were assessed using a microbiological assay for qualitative and quantitative determination of resistant bacteria in fecal samples of rats following gastric administration of the drug to rats for 4 consecutive days. Time- and site-controlled administration of a β-lactamase to the rat colon was assessed as a potential strategy for prevention the emergence of resistant bacteria following oral administration of incompletely absorbed antimicrobials. Results Emergence of resistant bacteria was demonstrated following oral administration of amoxicillin to rats, whereas de-activation of the β-lactam prior to entering the colon, by infusion of a β-lactamase into the lower ileum, was shown to prevent the emergence of resistant colonic bacteria. Conclusions This study illustrates the need to consider the emergence of antimicrobial resistance as a goal equally important to microbiological and clinical cure, when designing oral sustained-release delivery systems of antimicrobial drugs.     

Biofilms and antibiotic therapy: is there a role for combating bacterial resistance by the use of novel drug delivery systems?

The conventional view of antibiotic resistance is one where bacteria exhibit significantly reduced susceptibility to antimicrobials in laboratory tests by mechanisms such as altered drug uptake, altered drug target and drug inactivation. Whilst these mechanisms undoubtedly make a major contribution to antibiotic failure in the clinic, the phenomenon of clinical failure in spite of sensitivity in laboratory tests is also well recognised. It is in this context that attention has focussed on bacteria growing as adherent biofilms, not only as the mode of growth of device-related infections associated for example with artificial joints and venous catheters, but also with other chronic infections such as those occurring in the respiratory tract. Growth as a biofilm almost always leads to a significant decrease in susceptibility to antimicrobial agents compared with cultures grown in suspension and, whilst there is no generally agreed mechanism for the resistance of biofilm bacteria, it is largely phenotypic. That is, when biofilm bacteria are grown in conventional laboratory suspension culture they become susceptible to antimicrobials. A number of elements in the process of biofilm formation have been studied as targets for novel drug delivery technologies. These include surface modification of devices to reduce bacterial attachment and biofilm development as well as incorporation of antimicrobials-again to prevent colonisation. Electrical approaches have been used either to release antimicrobials from device surfaces or to drive antimicrobials through the biofilm. Other technologies not specifically focussed on biofilms include aerosolized delivery of antibiotics to the lung and formulation into liposome and polymer-based vehicles. Liposomal systems have been widely studied, either to target antibiotics to the surface of bacterial biofilms, or by virtue of their property of being taken up cells of the reticuloendothelial system, to target antibiotics towards intracellular bacteria. Many polymer-based carrier systems have also been proposed, including those based on biodegradable polymers such as poly(lactide-co-glycolide) as well as thermoreversible hydrogels. Their contribution to the prevention or resolution of infection is reviewed.     

Antimicrobial production by strictly anaerobic Clostridium spp.

Antimicrobial resistance continues to rise on a global scale, affecting the environment, humans, animals and food systems. Use of natural antimicrobials has been favoured over synthetic molecules in food preservation owing to concerns over the adverse health effects of synthetic chemicals. The continuing need for novel natural antimicrobial compounds has spurred research to investigate natural sources, such as bacteria, for antimicrobials. The antimicrobial-producing potential of bacteria has been investigated in numerous studies. However, the discovery of antimicrobials has been biased towards aerobes and facultative anaerobes, and strict anaerobes such as Clostridium spp. have been largely neglected. In recent years, genomic studies have indicated the genetic potential of strict anaerobes to produce putative bioactive molecules and this has encouraged the exploration of Clostridium spp. for their antimicrobial production. So far, only a limited number of antimicrobial compounds have been isolated, identified and characterised from the genus Clostridium. This review discusses our current knowledge and understanding of clostridial antimicrobial compounds as well as recent genome mining studies of Clostridium spp. focused at identification of putative gene clusters encoding bacterial secondary metabolite groups and peptides reported to possess antimicrobial properties. Furthermore, opportunities and challenges in the identification of antimicrobials from Clostridium spp. using genomic-guided approaches are discussed. The limited studies conducted so far have identified the genus Clostridium as a viable source of antimicrobial compounds for future investigations.     

Pharma now needs more than mergers

Fluoroquinolones, such as ciprofloxacin and ofloxacin have recently gained wide acceptance for use in the treatment of respiratory tract, skin/soft tissue, sexually transmitted diseases and urinary tract infections. The broad spectrum activity and good oral absorption characteristics of these antimicrobials promotes their use in both community and hospital settings. Despite these favourable properties, ciprofloxacin and ofloxacin have limited potency against some clinically important organsims, such as Streptococcus pneumoniae, enterococci and anaerobes including Bacteroides fragilis and many methicillin-resistant staphylococci. In addition, occasional clinical isolates of Enterobacteriaceae and Pseudomonas aeruginosa have emerged resistant to these compounds following their introduction. In an effort to expand upon the clinical utility of the existing fluoroquinolones, several new agents of this class have been identified and are in various stages of development. Some of these newer fluoroquinolones have significantly improved antimicrobial potency against the organisms mentioned above and/or possess pharmacokinetic characterisitics in humans that suggest they could be dosed less frequently than ciprofloxacin. This review will summarise the antimicrobial and human pharmacokinetic properties of sparfloxacin, clinafloxacin, PD-131628, PD-138312, PD-140248, Q-35, AM-1155, NM394, T-3761, rufloxacin, levofloxacin, CP-99,219, OPC-17116 and DU-6859a, which appear to be among the most interesting new fluoroquinolones currently in development. An attempt will be made to distinguish the most important characterisitics of these new agents, based upon the available preclinical data and results from single dose pharmacokinetic studies in humans. The data suggest that several of these fluoroquinolones possess properties that could translate into significant clinical advantages over the currently available compounds in this class.     

Intraoral drug delivery

The oral availability of many drugs is poor because of the pH of the stomach, the presence of enzymes, and extensive first-pass metabolism. Traditionally, these drugs have been administered as parenteral drug delivery systems, which invariably leads to poor patient compliance. This has made the pharmaceutical industry look for alternative routes of drug delivery. One possible route is via the oral cavity. This review compares the many different and novel drug delivery systems that have been developed for absorption through the oral cavity as well as those that undergo quick disintegration or dissolution in the oral cavity. Systems for oral delivery include mucoadhesive patches, films and tablets, as well as quick-disintegrating wafers, tablets and films. There are many examples of drugs that have been formulated into intraoral absorptive drug delivery systems as well as quick-disintegrating drug delivery systems. The fact that most of the research being conducted on intraoral drug delivery systems is driven by pharmaceutical manufacturers demonstrates the need for such drug delivery systems. As we begin to discover more about oral mucosal drug delivery, and develop much more sophisticated drug delivery systems, many more drugs will be formulated as intraoral systems. There is no doubt that the need for these systems is real, and many classes of drugs could benefit from this noninvasive type of drug delivery. The challenge now is to synthesize drug moieties that exhibit increased absorption across the oral mucosa and are more potent in their action. Intraoral drug delivery systems are possibly one of the very few drug delivery systems that seem to be ahead of the development of new drug compounds that are effectively absorbed across tissue membranes.