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Summary Background Recurrent Clostridioides difficile infection (CDI) is one of the most common and challenging infections to treat in healthcare facilities. Faecal microbiota transplantation (FMT) is recommended as a definitive treatment option. Methods We performed a retrospective review of 50 patients from January 2015 to December 2019 who underwent FMT for recurrent CDI. Primary outcome was recurrence of CDI within 12-weeks of FMT and secondary outcomes were the need for repeat FMT, serious adverse outcomes related to FMT and all-cause mortality. Results Fifty charts were reviewed, of which 47 cases comprising 17 immunocompromised patients treated with FMT via retention enema were included in the study. The majority of the patients had ≥3 recurrent CDIs (62%). Nine (19%) patients failed to respond to the first FMT and five underwent repeat FMT within four to 12 weeks. The cure rate was 81% after the first FMT (38/47) and 91% after the second FMT treatment (43/47). Serious adverse events occurred in 2% and all-cause mortality was 2% at 90-day follow up. Conclusion Our study demonstrated the safety and efficacy of FMT administered via retention enema, a simple bedside procedure, for the treatment and prevention of recurrent non-severe and severe CDI with an overall cure rate of 91%.

Antimicrobial resistance (AR) is escalating worldwide with the potential for dire consequences, global travel contributes to the dissemination of resistant pathogens from one region to another. The World Health Organization identified the rapid emergence and prevalence of carbapenem-resistant Gram-negative species, includingThis review describes key carbapenem-resistant (CR) Gram-negative species, changes in current global and regional trends, AR surveillance and reporting, and identifies drivers of change, specifically travel. Finally, we review clinical implications and challenges of treating CR infections which exist due to widespread dissemination of CR bacteria. A literature search was conducted using PubMed, Google Scholar, Ebsco, and ProQuest (from 2000 to December 2019).The level of global travel is increasing, and antimicrobial resistance continues to disseminate worldwide. Healthcare providers risk assessment for AR needs to consider a patient's recent travel history, including pre-travel and intra-travel antimicrobial prescription, and potential exposure based on geography. Patient education, healthcare provider awareness, and access to data and surveillance resources are critical to inform antimicrobial selection and improve health outcomes.

Omadacycline is a novel aminomethylcycline antimicrobial, US FDA approved for the treatment of community-acquired bacterial pneumonia and acute bacterial skin and skin structure infections. It is not susceptible to common tetracycline resistance mechanisms, and has demonstrated efficacy against a broad spectrum of pathogens including resistant isolates, which are increasing in prevalence and complexity. It is available in both intravenous and oral formats, and can be administered in single, once daily doses or multiple doses, with no dosing adjustments required for sex, age, hepatic or renal impairment. It can be a good option for patients with low treatment adherence, and oral therapy may be used to reduce length of hospitalization for iv. treatment. This article reviews the in vitro and in vivo activity, PK/PD profile, integrated data from clinical trials including clinical efficacy and safety profile, and looks to future application of omadacycline.

Over 25 years ago Professor Cookson [1] opined that ‘damage limitation policies such as control of antibiotic prescribing are the sensible way forward.‘ In an effort to provide such stewardship con...

Background Through improved understanding of the structure-activity relationship attributes of fluoroquinolones, molecule development has improved efficacy, safety, and tolerability of the class. Adverse events (AEs) associated with the fluoroquinolones are well defined and a prospective part of the development process. However, not all fluoroquinolones have the same AE profile with different substitutions on the core molecule resulting in differences in side effects and spectrum of activity. Unique structural attributes of delafloxacin (DLX) may differentiate its AE profile compared to other fluoroquinolones. This analysis compared the incidence of AEs between DLX and vancomycin/aztreonam across two phase 3 ABSSSI studies in order to provide a broader overview of DLX safety. Methods Safety events occurring in all subjects in the pivotal phase 3 trials were pooled to provide a broad overview of DLX safety. Results DLX was safe and well-tolerated in the pooled phase 3 ABSSSI trial population of 741 subjects. Treatment-emergent AEs (TEAEs) were seen in the DLX group versus the comparator group at 45.1% and 47.7%, respectively. Most were mild or moderate in severity. Treatment-related TEAEs were reported in the DLX group versus the comparator group at rates of 22.1% and 26.1%, respectively. Conclusions Available data show DLX is well tolerated in both intravenous and oral formulation for the treatment of ABSSSI and does not appear to be associated with increased risk of AEs associated with other fluoroquinolones. It remains important to monitor for potential AEs that have been observed with other fluoroquinolones.

As COVID-19 sweeps through the nation, turning hospitals into war zones, overwhelming healthcare personnel and essentially disrupting our healthcare framework, we envision the aftermath with cautio...

The emergence of antimicrobial resistance threatens current clinical practice across a range of infection types. Delafloxacin, a non-zwitterionic fluoroquinolone recently approved by the US FDA for the treatment of acute bacterial skin and skin structure infections, has been developed to address some of these challenges. Uniquely delafloxacin has increased intracellular penetration and enhanced antibacterial activity under acidic conditions, an environment seen in many infection sites including abscesses. Delafloxacin is active against a wide range of Gram-positive and -negative species including methicillin-resistant Staphylococcus aureus and many fluoroquinolone-resistant strains. Additionally, according to preclinical and clinical trial data, well-known adverse events related to fluoroquinolone class do not appear to occur with this new molecule. Delafloxacin has been studied in acute bacterial skin and skin structure infections with >1400 patients exposed to both intravenous and oral formulation for up to 14 days and has shown noninteriority to vancomycin with or without aztreonam. For its interesting microbiological and pharmacokinetic/pharmacodynamics characteristics and for its safety profile, delafloxacin represents a very promising option for the treatment of infections caused by multidrug-resistant pathogens.

We describe 9 patients at a medical center in Detroit, Michigan, USA, with severe acute respiratory syndrome coronavirus 2 and Clostridioides difficile. Both infections can manifest as digestive symptoms and merit screening when assessing patients with diarrhea during the coronavirus disease pandemic. These co-infections also highlight the continued importance of antimicrobial stewardship.

Antimicrobial resistance represents a significant global health threat. However, a commercial model that does not offer a return on investment resulting in a lack of investment in antibiotic R&D, means that the current pipeline of antibiotics lacks sufficient innovation to meet this challenge. Those responsible for defining, promoting and monitoring the rationale use of antibiotics (the antimicrobial stewardship programme) are key to addressing current shortcomings. In this personal perspective, we discuss the future role stewardship can play in stimulating innovation, a need to move away from a pharmacy budget dominated view of antibiotic use, and the impact of the ever-increasing sophistication and interdisciplinary nature of antimicrobial control programs. Changes are needed to optimize clinical outcomes for patients.

Although there was a flurry of new antifungal drugs approved in the early part of the last decade, the growing need for newer agents to treat systemic fungal infections has escalated due to increasing resistance to the 2 main classes of drugs developed to date and shifts in the etiology of these diseases. In addition to this microbial shift, there are more at-risk patients who are being managed in increasingly heroic ways and are thus highly susceptible to these more common resistant fungi and yeasts. However, as we acknowledge the need for new drugs to treat these desperately ill patients, there is a basic problem facing the pharmaceutical industry as it tries to balance the conundrum of antifungal development. Globally there is a relatively low, but growing, number of systemic fungal infections, which creates significant hurdles in conducting clinical trials in a timely and economical manner. In the United States, there have been some significant moves to easing these hurdles and, potentially, to bringing new drugs to the clinic more quickly and efficiently. We will discuss the current unmet clinical need and the current US regulatory positions to encourage further investment in this critical field.

Antimicrobial resistance has become a global problem. Many pathogens are becoming multidrug-resistant with the attendant increased risk of failure of standard therapies and the under-recognised outcomes such as increased morbidity, mortality, length of hospitalization and costs of treatment. Areas covered: We undertook a review of the literature using standard search engines including PubMed, Google Scholar, Scopus and internet sources. Key search terms included antimicrobial resistance, antibiotic resistance, bacterial resistance, clinical outcomes, economic consequences, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Streptococcus pneumoniae and Staphylococcus aureus. Expert commentary: Antimicrobial resistance among the five-species presented demonstrates a major, and increasing, deleterious impact seen in each of the key outcomes measured. These negative changes, at a personal, health system and Societal levels, further emphasise the growing problem of increasing antimicrobial resistance at a global level and the vital need for new antimicrobials.

Clostridium difficile infection (CDI) is the leading cause of infectious healthcare-associated diarrhoea. Recurrent CDI increases disease morbidity and mortality, posing a high burden to patients and a growing economic burden to the healthcare system. Thus, there exists a significant unmet and increasing medical need for new therapies for CDI. This review aims to provide a concise summary of CDI in general and a specific update on ridinilazole (formerly SMT19969), a novel antibacterial currently under development for the treatment of CDI. Owing to its highly targeted spectrum of activity and ability to spare the normal gut microbiota, ridinilazole provides significant advantages over metronidazole and vancomycin, the mainstay antibiotics for CDI. Ridinilazole is bactericidal against C. difficile and exhibits a prolonged post-antibiotic effect. Furthermore, treatment with ridinilazole results in decreased toxin production. A phase 1 trial demonstrated that oral ridinilazole is well tolerated and specifically targets clostridia whilst sparing other faecal bacteria. Phase 2 and 3 trials will hopefully further our understanding of the clinical utility of ridinilazole for the treatment of CDI.

The original and successful business model of return on investment being sufficiently attractive to the pharmaceutical industry to encourage development of new antibacterial molecules and related diagnostics has been compromised by increasing development costs and regulatory hurdles, resulting in a decreasing chance of success and financial return. The supply of new effective agents is diminishing along with the number of companies engaged in antibacterial research and development. The BSAC Working Party on The Urgent Need:Regenerating Antibacterial Drug Discovery and Development identified the need to establish, communicate and apply the true health and economic value of antibacterials, along with the adoption of meaningful incentives, as part of the future model for antibacterial development. Robust data are needed on the cost of resistance and ineffective treatment of bacterial infection, along with national and local holistic analyses of the cost-benefit of antibacterials. An understanding of the true health and economic value of antibacterials and the cost of resistance across healthcare systems needs to be generated, communicated and used in order to set a pricing and reimbursement structure that is commensurate with value. The development and economic model of antibacterial use needs to be rebuilt based on this value through dialogue with the various stakeholders, including the pharmaceutical industry, and alternative incentives from 'push' to 'pull' and funding models, such as public/private partnerships, agreed. A research and development model that succeeds in developing and delivering new antibacterial agents that address the health needs of society from start to finish, 'from cradle to grave', must be established.

Physicians need a better understanding of outcomes of these infections., We evaluated the annual rate (cases/10,000 hospitalizations) of pediatric hospitalizations with Clostridium difficile infection (CDI; International Classification of Diseases, 9th revision, clinical modification code 008.45) in the United States. We performed a time-series analysis of data from the Kids’ Inpatient Database within the Health Care Cost and Utilization Project during 1997–2006 and a cross-sectional analysis within the National Hospital Discharge Survey during 2006. The rate of pediatric CDI-related hospitalizations increased from 7.24 to 12.80 from 1997 through 2006; the lowest rate was for children

The use of noninferiority clinical trials is problematic unless one can establish the benefit of the active control versus no treatment. In community-acquired pneumonia, there are no placebo-controlled clinical trials establishing the benefit of antibiotic treatment, because the observed benefit of sulfapyridine and, subsequently, penicillin was established before the advent of randomized clinical studies. Historical data and observational cohort studies have established the marked decrease in mortality resulting from antimicrobial therapy; however, mortality is not a suitable end point for contemporary clinical trials for mild-to-moderate community-acquired pneumonia that is treated with oral antimicrobial drugs in ambulatory patients. There are historical clinical data that describe the timing of spontaneous recovery in patients with documented pneumonia caused by Streptococcus pneumoniae. In addition, there is one contemporary clinical trial that demonstrated superiority in clinical response of levofloxacin versus a cephalosporin regimen of ceftriaxone and/or cefuroxime for treatment of mild-to-moderate community-acquired pneumonia. Using either the historical data or the superiority study of levofloxacin, one can justify a noninferiority margin of 10% for the per-protocol population and 15% for the microbiologically evaluable population for future noninferiority clinical trials for mild-to-moderate community-acquired pneumonia.

The appropriate management of Clostridium difficile infection (CDI) has become a growing clinical and economic issue, as a new epidemic strain with enhanced virulence is causing increased morbidity and mortality. Presently, only two antibiotics (metronidazole and vancomycin) are routinely used to treat CDI. Both increasing disease severity and recurrent infections have been an impetus not only to develop new agents, but also to better recognize which patients are at highest risk for treatment failure and/or recurrence so that treatments can be optimized from the outset. The availability of a standardized and validated system for stratifying CDI severity could improve patient management and potentially accelerate the development of new treatment agents.

Antibiotic development has decreased significantly, in part because of recent changes in regulatory requirements in the United States. These changes both decrease the probability of technical and regulatory success for a new antibiotic for which marketing approval is sought and motivate the pharmaceutical industry to focus its research efforts on other therapeutic areas. There is a growing, unmet clinical need for new antibiotics, because of bacterial resistance to approved drugs; however, there are few candidates in development, especially new oral agents for treatment of community-acquired respiratory infections. The answers to important questions about the benefit of antibacterial treatment for community-acquired pneumonia and the publication of clear guidance for future clinical studies will support future investments. We discuss the underlying issues and offer some alternative strategies to enable improvements in clinical trial design for community-acquired pneumonia.

Respiratory tract infections (RTIs) form a substantial clinical and financial burden, with the increasing complication of antimicrobial resistance. This resistance may compromise the use of many empirically prescribed antimicrobials. The new respiratory fluoroquinolones have been developed to overcome this burgeoning resistance. This group includes gemifloxacin, an enhanced-affinity fluoroquinolone that has been approved for clinical use in several countries and is characterised as a potent dual-acting agent with excellent in vitro activity against Streptococcus pneumoniae (minimum inhibitory concentration for 90% of strains (MIC90)=0.03-0.06 microg/mL). Gemifloxacin given once daily for 5-7 days has been shown to be non-inferior to, or in some instances superior to, comparator agents for the treatment of common lower RTIs. Moreover, it is generally well tolerated and is as safe as many frequently empirically prescribed antimicrobials. In addition, studies have shown gemifloxacin to be a cost-effective agent for some lower RTIs.

The aim of this study was to describe the rates of antimicrobial susceptibility of Staphylococcus aureus from skin and wound infections reported from nine regions of the USA during 2005-07 and to identify the regional variation in patterns of resistance.The Surveillance Network (TSN) comprises 296 laboratories across the nine census regions of the USA. TSN laboratories reported the susceptibility data for six antimicrobials by isolate with source and other relevant data. Antimicrobial susceptibility data were analysed by individual drug resistance, multidrug resistance and geographical distribution of resistance phenotypes.There were over 380 000 isolates of S. aureus tested and reported for the period 2005-07. Methicillin resistance was observed in 57.8% in 2007, with little change from 2005. There was little difference in rates of methicillin resistance between community and hospital strains, although strains from intensive care units (ICUs) tended to be slightly more resistant overall. Resistance to other antimicrobials was also reported. A regional variation in resistance rates was noted with the highest rates in the Central states and lowest in the New England and Mid-Atlantic regions. There was high activity observed with trimethoprim/sulfamethoxazole and gentamicin. Linezolid resistance was rare. Oxacillin resistance was similar among paediatric and elderly cohorts, whereas ciprofloxacin and clindamycin resistance was significantly (P0.01) more common in elderly patients when compared with both paediatric and adult populations. Less than a third of all isolates showed no resistance mechanism, 30.3%. Three distinct resistance phenotypes accounted for 46% of all resistant strains. Overall, there were more highly drug-resistant isolates from the ICU with four, five or six drug-resistant phenotypes accounting for over a third of all strains.S. aureus has become methicillin-resistant in both the community and hospital settings; however, little change has been seen in the past 3 years. Multiresistant strains now are seen in all settings, but due to regional variation, empirical therapy should be guided by local susceptibility patterns. Currently, among the agents studied, only trimethoprim/sulfamethoxazole, gentamicin and linezolid exhibit susceptibility rates of95%.

Over 420 delegates participated in this, the fourth of a biennial series of scientific meetings, drawing from 30 or more nations and encompassing the specialties of infectious diseases, clinical microbiology, pulmonary and general medicine and Industry inter alia. The 2007 Forum was chaired by Professors Antoni Torres Marti, Giuliana Gialdroni Grassi and Dr Peter Ball and received academic endorsement from the British Society for Antimicrobial Chemotherapy (BSAC), Italian Society for Chemotherapy, Spanish Pulmonology Society, Paul Ehrlich Society and the Societe de Pneumologie de Langue Francais. The Scientific Programme was scientifically and financially supported by the BSAC and a consortium of pharmaceutical companies. Discussion focused on key contemporary issues in respiratory tract infection (RTI), including the impact of antibiotic resistance on clinical outcomes and the continuing need for antibiotic conservation via evolving guidelines, the challenges of avian influenza, nosocomial RTIs and the emergence of new pathogens, e.g. community-acquired methicillin-resistant Staphylococcus aureus, novel antimicrobial agents, disease definitions (e.g. healthcare-associated pneumonia) and therapeutic assessment criteria, such as patient-reported outcome measures, in improving RTI management. The entire meeting was granted CME recognition (18 sessions) by the European Accreditation Council for continuing medical education.

Antimicrobial resistance is an increasing problem worldwide in both the hospital and community settings. Various approaches have been proposed and tested mainly in the hospital environment to reduce this problem; however, few of these have been examined from the perspective of applicability to reversing community-based resistance. It is clear that, in addition to specific antibiotic usage campaigns, a major educational initiative for both prescribers and patients alike is required for the full societal impact of growing antibiotic resistance to be appreciated. This inexorable increase is occurring in the face of a dearth of new antibiotics for community use and even fewer for treating resistant nosocomial gram-negative species. The possible strategies and consequences are discussed.

Surveillance initiatives to track Streptococcus pneumoniae resistance trends are important for understanding the current in vitro effectiveness of available antimicrobial agents. The antimicrobial susceptibility profiles of S. pneumoniae ( n = 1479 isolates) collected from 17 geographical areas across the USA (2003–2004) were analysed; 36.8% of isolates were resistant to one or more agents (24.4% were multidrug-resistant, i.e. resistant to two or more antimicrobial classes). Multidrug resistance involved resistance to β-lactams, macrolides, tetracycline and trimethoprim/sulphamethoxazole, but rarely fluoroquinolones (>96% of multidrug-resistant isolates were fluoroquinolone-susceptible). Multidrug resistance rates were prominent regardless of the geographical region surveyed. As this trend continues, the empirical therapeutic options for S. pneumoniae infections will diminish and there will be an ongoing need to evaluate the effectiveness of potent fluoroquinolones such as gemifloxacin.

Heavy antibiotic usage is thought to contribute to the increased bacterial antibiotic resistance reported in intensive care units. Many units use extended-spectrum cephalosporins or fluoroquinolones as the empirical drug of choice; however, there are few reports documenting the effects of a switch from one class of antibiotics to another. A 2-year crossover study was undertaken on 2 large units, where the ecological effect of the implementation of a defined prescribing policy of 2 different antibiotic classes on the microflora of patients was examined. For the first year, cefotaxime or ceftazidime was the drug of choice for empirical treatment of patients. In the second year, this was changed to ciprofloxacin. Bacterial isolates from twice-weekly surveillance specimens and all clinical specimens were collected from 1026 patients. These were identified, and breakpoint susceptibility testing was conducted both during a 3-month baseline period and during the 2-year study period. Patient demographic data and antibiotic usage data were recorded throughout the study. There was a significant increase in the amount of ciprofloxacin used in the second year of the study and a decrease in the amount of cefotaxime or ceftazidime used. The decreased use of cephalosporins was linked with a decrease in ceftazidime-resistant Enterobacteriaceae organisms. The increased use of ciprofloxacin during the second year of the study did not seem to cause any significant rise in ciprofloxacin-resistant isolates. Although reducing the overall selective pressure by cutting antibiotic usage is important for controlling antibiotic resistance, our study illustrates the value of carefully considering which classes of antibiotic should be used for empirical therapy.

Increasing resistance in Pseudomonas aeruginosa to multiple antibiotics has been observed and is posing therapeutic dilemmas. Antibiotic utilization is one factor that has been associated with the emergence of antimicrobial resistance. We examined the overall and specific antimicrobial use in relation to changes in susceptibility patterns in P. aeruginosa. Regression analysis was performed to explore the relationships between annual antibiotic use and the incidence of resistant P. aeruginosa. There were statistically significant relationships between increasing anti-pseudomonal cephalosporin and levofloxacin use and the increasing incidence of ciprofloxacin resistant P. aeruginosa. However, there was not an association between other fluoroquinolone or overall fluoroquinolone use and this change. In addition, there was no association between increasing anti-pseudomonal cephalosporin use and cefepime resistant P. aeruginosa. No statistical relationship was seen with overall antibiotic use and the development of resistance in P. aeruginosa, suggesting that the development of resistance is associated with the use of individual agents, rather than overall antibiotic consumption.

Community-acquired lower respiratory tract infections (LRTIs) are more prevalent in the elderly than in children and younger adults and form a significant proportion of all consultations and hospital admissions in this older age group. Furthermore, in a world of increasing life expectancy the trend seems unlikely to be reversed. Antimicrobial treatment of community-acquired pneumonia (CAP) must cover Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis, and in many circumstances should also cover the intracellular (atypical) pathogens. In contrast, acute exacerbations of chronic bronchitis (AECB) are mainly associated with H. influenzae and S. pneumoniae and not with atypical bacteria: in severe cases, other Gram-negative bacteria may be involved. Frequently in LRTIs, the aetiology of the infection cannot be identified from the laboratory specimens and treatment has to be empirical. In such situations it is important to not only to use an antibiotic that covers all likely organisms, but also one that has good activity against these organisms given the local resistance patterns. Gemifloxacin is a new quinolone antibiotic that targets pneumococcal DNA gyrase and topoisomerase IV and is highly active against S. pneumoniae including penicillin-, macrolide- and many ciprofloxacin-resistant strains, as well as H. influenzae and the atypical pathogens. In clinical trials in CAP and AECB, gemifloxacin has been shown to be as effective a range of comparators and demonstrated an adverse event profile that was in line with the comparator agents. In one long-term study in AECB significantly more patients receiving gemifloxacin than clarithromycin remained free of recurrence after 26 weeks. The improved potency, broad spectrum of activity and proven clinical and bacteriological efficacy and safety profile should make it a useful agent in the 21st century battle against community-acquired LRTIs.

This review focuses on the activity of gemifloxacin, a new respiratory fluoroquinolone, against the two most important bacterial pathogens associated with lower respiratory tract infections, namely Streptococcus pneumoniae and Haemophilus influenzae.

In 1991, Karchmer [1] raised several key issues related to the pathogenesis and optimal treatment of Staphylococcus aureus infections. The main issue concerned the role of vancomycin in treating serious or invasive methicillin-sensitive S. aureus ( MSSA) and methicillinresistant S. aureus (MRSA) infections. He recognized and envisaged the current global epidemic of MRSA infections in hospitals [2], and to a lesser extent the community [3], and concluded that ‘there is an urgent need for effective alternatives to vancomycin for the treatment of MRSA infections’. Since then we have emerging evidence, a recent meta-analysis, that in patients with S. aureus -related bacteraemia, MRSA is an independent risk factor for higher mortality compared with MSSA bacteraemia [4]. This adds further support to the ongoing debate about the virulence of MRSA infections compared with MSSA and the need for optimal antibiotics at the onset of treatment. The reality, a decade later, is the occurrence of a broad range of serious and invasive MRSA infections, often in vulnerable patients in ‘high risk’ clinical settings [5]. The need to treat many of these patients empirically with a view to ‘covering’ the most likely offending pathogens is perceived to be high if the critical therapeutic window of opportunity for optimal antibiotic therapy is not to be missed. The undesirable consequences of not getting the ‘right drug, to the right patient, in the right dose at the right time’ are clear [6]. The rapid laboratory and clinical capability of predicting patients likely to be infected with MRSA continues to improve but is by no means ideal [7,8]. Additionally, we are witnessing the concurrent rise in S. aureus strains that exhibits glycopeptide-intermediate susceptibility from several countries including Japan, France and US that has been subject to recent review [9]. For example, strains with MIC to vancomycin of 4 mg/l have caused clinical infections that failed to respond to vancomycin therapy. Traditionally, when the effectiveness of an antimicrobial agent in serious infections is considered, there has been an overemphasis on the need for bactericidal activity as a pre-requisite for a good outcome. Many of us now accept that local tissue penetration should be considered of equal importance. This is particularly important when looking at treatment options for staphylococcal infections, especially in tissues such as lung or the endovascular lining. Vancomycin is still regarded as the ‘gold-standard’ therapy for serious or invasive MRSA infections. Considering Karchmer’s concerns of a decade ago, we examine what more have we learnt about vancomycin treatment and summarize the emerging evidence for new or combination therapies. Vancomycin is bactericidal and appears to exert its effect by binding to the precursor units of peptidoglycan synthesis inhibiting the transpeptidase reaction. It exhibits concentration-independent bactericidal action against susceptible bacteria and is more bactericidal in aerobic conditions. This effect is exerted without a lag period but acts only on multiplying organisms and with a post-antibiotic effect of about 2 h. Against MSSA, it is a less active agent than b-lactams [1,10 /12] by virtue of being more slowly and incompletely bactericidal compared with equivalent concentrations of a b-lactam. A recent illustration of this phenomenon in clinical practice was demonstrated by Tam et al. [13] in haemodialysis patients with MSSA bacteraemia. This study revealed that persistent bacteraemia 24 h after therapy was significantly greater (37% vs. 25%, P /0.05) in patients initially treated with vancomycin compared with those with a b-lactam. Additionally, in patients with MSSA endocarditis and related bacteraemia, there * Corresponding author. Tel.: /44-1382-660-111; fax: /44-1382816-178. E-mail address: dilip.nathwani@tuht.scot.nhs.uk (D. Nathwani). International Journal of Antimicrobial Agents 21 (2003) 521 /524

Changing patterns of pathogens and antibiotic susceptibility present clinicians with difficult choices for antimicrobial prescribing. In particular, multiresistant staphylococci, enterococci and pneumococci present problems in many settings. The number of predictably active antimicrobials is decreasing in many centres, with significant consequences for both patients and society as a whole. New antimicrobial options have been few in recent years and several promising quinolones have been compromised by formulation and/or toxicity issues. Nevertheless, the recent introduction of linezolid and quinupristin/dalfopristin provides clinicians with valuable new options against Gram-positive cocci. These options should further increase with the likely introduction of daptomycin, oritavancin and tigilcycline. A range of surveillance programmes helps monitor the ever-changing patterns of resistance and thus guides clinicians in their empirical prescribing. Empirical use of powerful newer agents may be justifiable in seriously ill patients in those settings, units and countries where there is a substantial background rate of resistance.

Streptococcus pneumoniae is a significant pathogen of respiratory tract infections such as pneumonia, sinusitis, meningitis, and acute otitis media. Rising incidences of antimicrobial resistance among pneumococcal strains reported worldwide have led to research into and development of advanced antibacterials with improved gram-positive activity. Moxifloxacin, a new 8-methoxy quinolone, has been tested against a variety of S. pneumoniae strains, including penicillin-sensitive, intermediately resistant to penicillin, and penicillin-resistant strains. We review the preclinical data corroborated by the available clinical experience to demonstrate moxifloxacin's activity against S. pneumoniae strains, irrespective of penicillin susceptibility.

Moxifloxacin is a new broad-spectrum antibacterial agent for treatment of respiratory tract infection of pathogens, including the major pathogens isolated in respiratory tract infections. The pharmacokinetic and pharmacodynamic properties of moxifloxacin are: excellent bioavailability, long half-life, and superior tissue penetration. Consequently, the 90% minimum inhibitory concentration (MIC(90)) values exhibited by moxifloxacin are generally lower than the concentrations of moxifloxacin found in circulation and in pulmonary tissues after a standard 400-mg dose given for up to 30 h. The relationship between moxifloxacin MIC(90) values and clinical response was investigated. The results of 13 clinical trials, performed in 30 countries between 1997 and 1998 and comprising 2618 patients treated with moxifloxacin or a comparator drug, were reviewed. Overall, 94% clinical success and 95% bacterial eradication was observed with moxifloxacin. These results were equivalent or superior to results seen with the comparator drugs. Clinical response rates and bacterial eradication rates with moxifloxacin were not significantly affected by bacterial resistance to other antibiotics (i.e., penicillin, clarithromycin, or amoxicillin). The majority (89%-97%) of the different bacterial strains with MICs for moxifloxacin < or =2 mg/L were successfully eradicated. In conclusion, moxifloxacin has potent in vivo bactericidal activity, and pathogen sensitivity to moxifloxacin is in accordance with US Food and Drug Administration and European suggested breakpoint values.

Sequential antimicrobial therapy (SAT) is arousing keen interest in microbiologists and pharmacists. In an attempt to obtain information from these groups regarding the use of SAT in hospitals, an anonymized postal survey was carried out. A SAT questionnaire was circulated to consultant medical microbiologists, clinical microbiologists, and heads of pharmacy departments within the British Isles. Four hundred and forty-seven microbiologists and pharmacists returned completed questionnaires, giving a response rate of 29%. Just over half of medical microbiologists (MM) and pharmacists (PH) indicated that SAT was used in their institution in respiratory medicine, geriatrics, surgery and, significantly, to a lesser degree in paediatrics. The most common infections treated were pneumonia, bronchitis and wound infection. However, there were significant differences between MM and PH, with MM favouring greater use of SAT in peritonitis (P=0.03), septicaemia (P0.01), bone infection (P0.01), pyelonephritis (UTI) (P0.01), and PH favouring use in bronchitis (P0.01). The ability to take oral fluids or a recognition of no potential absorption problems were key criteria in the decision process leading to the institution of SAT by MM and PH. Significantly more MM favoured employing criteria such as temperature38 degrees C (P0.01), no requirement for high tissue concentrations (P=0.02) and evidence of response to i.v. antimicrobial therapy (P0.01) than PH. The most frequently "switched" antimicrobials were metronidazole, ciprofloxacin and co-amoxiclav. There were more than five times as many MM reporting the use of clindamycin than PH (P0.01), whereas nearly twice as many PH cited use of cefuroxime (P0.01). Of those hospitals not employing SAT, most MM and PH concurred that the commonest reason to institute SAT was financial, followed by convenience to patients and staff. However, more PH than MM indicated that protocols (P0.01) and a reduction in i.v. complications (P0.01) were important to them. In promoting SAT, MM and PH felt they had the major role. Significantly, each profession felt that the other had a lesser role to play; MM as judged by the PH (P0.01) and PH as judged by MM (P0.01). When promoting SAT, both MM and PH felt that "education for clinicians" followed by regular audit was the best way to ensure implementation. However, significant differences arose with PH regarding nurse education (P0.01), SAT posters (P=0.02), regular review of patients (P=0.04) and patient's notes SAT stickers (P0.01) as more important to them than MM. Significantly, less MM than PH (P0.01) insisted that either the i.v. and PO antimicrobials were identical or were from the same group or class when "switching". This survey highlights interesting comparisons between the approaches of MM and PH towards SAT and may indicate ways in which both groups may work together to bring about change.

The challenges of evolving bacteria and emerging antibacterial resistance have presented many hurdles over the past 50 years. However, many experts are becoming concerned with the lack of innovatio...

Background. The demographic and subsequent economic pressures in developing nations have contributed to the increasing levels of antibiotic resistance among both commensal flora and pathogenic bacteria. As empirical options are diminishing daily, the role of ciprofloxacin in pediatric infections is becoming increasingly significant. Objective. The levels of resistance among various enteric pathogens are described, and the efficacy and safety of ciprofloxacin in treating infections such as shigellosis, cholera and Escherichia coli gastroenteritis are discussed. The findings of a large study of invasive salmonellosis in children in rural Africa are briefly presented, including the role of ciprofloxacin in multiresistant invasive disease. In addition the role of ciprofloxacin as a chemoprophylactic agent in the control of meningococcal disease is discussed. Results. The efficacy and safety of ciprofloxacin in children were found to be similar to those observed in adults for gastrointestinal infectious diseases. Overall the data presented confirm that ciprofloxacin is a safe and efficacious agent for use in children in the developing world. Conclusion. Ciprofloxacin has been shown to be safe and efficacious in children in developing countries. Subsequently a priority for both the pharmaceutical industry and regulatory authorities in developing nations is to prevent fluoroquinolone misuse and development of antibiotic resistance.

Development of the first clinically useful quinolone - nalidixic acid - occurred in 1962, but the significant breakthrough with this class of agents occurred almost 20 years after the original discovery when the addition of a fluorine molecule at position C6 of the pharmacore created the ‘fluoroquinolones’. It has been estimated that over 10 000 analogues of nalidixic acid or the fluoroquinolones have now been synthesised. The benefits of some of these new compounds include: oral and parenteral dosing, a much broader spectrum of antibacterial activity, good tissue distribution, improved pharmacokinetic profiles, stability and a comparatively low incidence of adverse effects. This review considers the structure of the core fluoroquinolone molecule, some of the changes that feature on current class members under development, and the effects that these chemical modifications may have on the interaction of these compounds with man.

One hundred and fifty patients undergoing gastroduodenal surgery were randomly allocated to receive intravenous (iv) cefuroxime, iv ciprofloxacin or oral ciprofloxacin as prophylaxis. There were no differences in the incidence of postoperative infection complications or duration of stay among the three groups. Oral ciprofloxacin offers obvious advantages in terms of ease of administration and cost.

Staphylococcus aureus mutants resistant to ciprofloxacin were selected both in vitro and in vivo. In-vitro selection was achieved by incubating two strains of S. aureus (MICs of ciprofloxacin of 0.5 and 4 mg/L respectively) in the presence of ciprofloxacin in concentrations equivalent to 1/2 x MIC for 24 h and isolating the mutants on agar containing the quinolone at 1, 2 or 5 x MIC. Stably-resistant mutants of both strains were isolated, although the frequency of mutation of the susceptible strain was higher than that of the resistant strain. A murine subcutaneous abscess model was used for in-vivo selection. Mice which had been infected with a ciprofloxacin-susceptible strain of S. aureus were treated for 24 h with ciprofloxacin in a dosage which yielded concentrations in the abscess cavity equivalent to 1/2 or 1 x MIC for the pathogen. Additional groups of infected mice received ciprofloxacin for varying periods in a dosage which produced concentrations at the site of infection equivalent to 1/2 x MIC. Stably-resistant mutants were isolated from the abscesses, the number of mice from which mutants were isolated and the mutational frequency being inversely proportional to the dosage of ciprofloxacin administered and the duration of treatment. The results of this study confirm that, in the treatment of patients with infections caused by S. aureus, the dosage of ciprofloxacin should be adequate to ensure inhibitory concentrations at the site of infection.

Sterile culture filtrates from non-typable Haemophilus influenzae (NTHi) grown in medium containing no antibiotics or 0.25 MIC of amoxycillin, ciprofloxacin or loracarbef were examined for their effect on the ciliary beat frequency (CBF) and structure of human respiratory epithelium. CBF slowing was significantly (P < 0.05) less with 0.25 MIC of all three antibiotics. The epithelium was significantly (P < 0.05) less disrupted with ciprofloxacin. The morphology of NTHi infecting human adenoid organ cultures after 24 h with or without 0.25 MIC of the same antibiotics was measured by scanning electron microscopy. Only ciprofloxacin caused a significant (P < 0.05) change in morphology.

The dwindling supply of new antibiotics largely reflects regulatory and commercial challenges, but also a failure of discovery. In the 1990s the pharmaceutical industry abandoned its classical ways of seeking antibiotics and instead adopted a strategy that combined genomics with high-throughput screening of existing compound libraries. Too much emphasis was placed on identifying targets and molecules that bound to them, and too little emphasis was placed on the ability of these molecules to permeate bacteria, evade efflux and avoid mutational resistance; moreover, the compound libraries were systematically biased against antibiotics. The sorry result is that no antibiotic found by this strategy has yet entered clinical use and many major pharmaceutical companies have abandoned antibiotic discovery. Although a raft of start-up companies-variously financed by venture capital, charity or public money--are now finding new antibiotic compounds (some of them very promising in vitro or in early trials), their development through Phase III depends on financial commitments from large pharmaceutical companies, where the discouraging regulatory environment and the poor likely return on investment remain paramount issues.