Search

Everyone is aware that antibiotic resistance is a major clinical, and economic, problem. Recent publications have foretold huge costs and clinical disasters if we do not better manage the tools we ...

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.

Hereditary angioedema (HAE) is a rare inherited disorder of complement factor C1 inhibitor. In 2007 there were over 2000 HAE-related emergency department (ED) visits, nearly one-half of which culminated in a hospitalization. This study examines epidemiology and outcomes of hospital ED visits among HAE patients. We evaluated epidemiology, resource use, and discharge destinations of HAE (International Classification of Diseases, Version 9, clinical modification [ICD-9-CM] code 277.6) ED visits within the Nationwide Emergency Department Sample, part of Agency for Healthcare Research and Quality Healthcare Costs and Utilization Project, in 2006 and 2007. In 2006-2007, there were 5040 ED visits with HAE, of which 2705 (53.7%) had HAE as the principal diagnosis (HAE-PD). The mean age for all HAE visits was 38.2 years, and women accounted for 56.5% of all HAE visits. When HAE was not the primary reason for the visit, abdominal pain was the most prevalent (10%) presenting diagnosis. Two thousand fifty-nine (40.9%) resulted in a hospitalization. Although of all HAE ED visits that did not require a hospitalization, the vast majority was discharged routinely home, further care either at a skilled nursing facility or at home was required after 45 (0.9%) of all the HAE visits and 10 (0.4%) of the HAE-PD visits. Mean HAE ED visits costs were $1479 (95% confidence interval, $1028-1929). HAE ED visit volume is substantial. Although likely representing a fraction of the entire HAE population, prevention and acute treatment strategies aimed at those at risk for frequent exacerbations and disproportionate resource use need to be examined.

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.

Hereditary angioedema (HAE) is a rare inherited disorder of complement factor C1 inhibitor. There are ∼6000 HAE cases in the United States, nearly one-half of whom suffer a monthly exacerbation. Little is known about hospital use patterns by patients with HAE attacks in the United States. This study was designed to examine burden, epidemiology, and outcomes of hospitalizations among HAE patients. We evaluated epidemiology, resource use, and discharge destinations of HAE (ICD-9-CM code 277.6) hospitalizations within the NIS, part of Agency's for Healthcare Research and Quality Healthcare Costs and Utilization Project in 2004 through 2007. There were 10,125 hospitalizations with HAE, of which 3216 (31.8%) had HAE as the principal diagnosis (HAE-PD). Two-thirds of all HAE hospitalizations were among women, and 60% were white. Hypertension was the most common comorbidity (26.9%, all HAE, and 28.0%, HAE-PD). Mortality was 1.4% in HAE and 0.3% in the HAE-PD group. Mean hospital length of stay (3.7, 95% CI 3.0-4.4 days vs. 5.0, 95% CI 4.6-5.4 days) and costs ($4,760, 95% CI $3,612-$5,907 vs. $8,383, 95% CI $7,432-$9,334) were lower in HAE-PD than in the HAE cohort. Although >80% in each group were discharged home routinely, 15.9% of HAE and 4.9% of HAE-PD required either home health care or a transfer to another short-term hospital or a skilled nursing facility. HAE hospitalization volume is substantial. Because diagnostic uncertainty is likely, HAE and its related resource use may be underestimated. HAE prevention strategies need to be examined in the context of these outcomes.

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%.

Bacterial resistance is a global issue accentuated by growing migration and international travel. Resistant pathogens, which were once considered local phenomena, are now spreading around the globe with astonishing speed. The recent O’Neil report has predicted dire consequences unless we act soon and effectively. The scenario for 2050 is incredibly daunting with significant negative economic and mortality outcomes. The current and future prospects were discussed at a UN Summit in New York City on September 22 with the consensus agreeing that, indeed, this is a global crisis. However, there needs to be a concerted, harmonized effort to tackling the escalating problem. Perhaps projects supported by individual nations, or even continents could be better maximized if there was a singular body driving a coordinated series of programs. There are various agreements in place, supporting initiatives between USA and Europe and USA and Asia, but could we make even more progress if we actually all worked together. As I mentioned earlier bacterial resistance is a global crisis so why not combat it together? Perhaps the International Committee for Harmonization could assume a leadership role as they have done in establishing protocols for specific parameters as QT prolongation (ICH E14) or maybe the World Health Organization could step in to maximize the global resources which are, and could be available?

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.

Background The majority of community-acquired pneumonia (CAP) patients (about 80%) will be treated as outpatients, because therapy with a single agent will work. For the remaining 20% of patients requiring hospitalization, there is some growing debate regarding the efficacy of different management approaches. For hospitalized patients, monotherapy with a respiratory fluoroquinolone agent seems to be gaining popularity, but dual therapy combining a β-lactam and an advanced macrolide still represents a good choice. Indeed, this regimen was recommended for all of the inpatient categories in the latest Infectious Disease Society of America CAP guidelines in 2003 Aim The purpose of this review was to examine the current clinical evidence to support one option or the other by gathering all of the available published literature. We will review the existing controversies in terms of microbiology, immunology, and clinical outcomes comparing dual therapy ( ie , with any combination of β-lactams, macrolides, or fluoroquinolones) with monotherapy in the treatment of CAP Results For the vast majority of patients with CAP ( ie , outpatients and inpatients on medical wards), the type of antibiotic regimen prescribed does not have any significant impact. For patients with severe pneumonia, for which there is no accepted definition so far, the controversy remains alive. Mortality from pneumococcal pneumonia has been reduced over the last decades, but despite improved medical care, bacteremic pneumococcal pneumonia is still as lethal as ever, probably because of the aging population, the greater number of immunocompromised patients, and the number of patients with frequent comorbid conditions. Worldwide, the increasing rates of resistance of Streptococcus pneumoniae to antibiotics are also a serious concern, and the clinical implications are not always obvious. Although limited in number, the four studies showing the importance of adding a macrolide to a β-lactam regimen for the treatment of bacteremic S pneumoniae pneumonia are retrospective and nonblinded, the findings are consistent, and they point to a trend that has to be explored more thoroughly. Studies published in the last few years suggest that combination therapy may be superior for bacteremic S pneumoniae pneumonia Conclusion In the meantime, for practical purposes, patients hospitalized with a diagnosis of severe CAP may benefit from a dual antibiotic therapy combining a third-generation cephalosporin and a macrolide. For the majority of hospitalized patients with CAP who are not severely ill, fluoroquinolone monotherapy remains an approved, tested, and reliable option. Indeed, the time for more aggressive outpatient fluoroquinolone therapy may reduce the number of patients who are hospitalized with CAP. Independent prospective studies comparing combination therapy with standard monotherapy are urgently required for hospitalized patients with severe CAP

Lower respiratory tract infections account for over 50 million deaths each year globally. They exert a growing clinical and financial burden on healthcare systems and employers. The increasing prevalence of antimicrobial resistance among usual bacterial pathogens over the past 10 years further drives this burden of disease. Typically, species such as Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis exhibit differing, but still growing, resistance phenotypes. The impact of resistance has only recently been fully appreciated, with clinical failures to many first-line agents being reported, as well as eminent groups acknowledging the financial impact of bacterial resistance. As resistance continues to emerge, it is recognized that a successful clinical outcome depends upon several factors including the patient, selection of appropriate drug and local epidemiology of the likely pathogen. Treatment failures will lead to repeat physician visits, extra diagnostic and laboratory tests, f...

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.

The current document bestows an expert synopsis of key new information presented at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting in 2003. Data is presented on the socio-political aspects of and policies on antimicrobial prescribing, novel mechanisms of resistance in Streptococcus pneumoniae, and current epidemiological trends in global resistance. Novel information on new (and existing) antimicrobial agents--new penicillins, cephalosporins, monobactams and oxipenem inhibitors, ketolides, glycopeptides, fluoroquinolones (and hybrids), peptides, daptomycin, aminomethylcyclines, glycylcyclines, and newer formulations of agents such as amoxycillin-clavulanate--provides renewed hope that resistant pathogens can be controlled through use of more potent agents. Improved strategies for the use of existing antimicrobial agents, such as the use of high-dose regimens, short-course therapy, also may delay or reduce the development of resistance and preserve the value of our antibiotic armamentarium.

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

It is evident that few classes of drugs have made such a remarkable impact on human health as antibiotics. The marked drop in mortality, serious sequelae and overall benefit to society due to decreased morbidity. However in the past few years it has become clear that we are on the verge of a major public health crisis as bacterial resistance to many of the routine antibiotics is nullifying their effects and benefits. The Director-General of the World Health Organization [1] as well as the Chief Medical Officer of the United Kingdom [2] predicted that the impact of growing resistance will severely impact modern medicine. Our ability to perform routine medical procedures such as joint replacements and cardiac surgery will be curtailed and perhaps most frightening is the emergence of Multi-Drug Resistant (MDR) pathogens which will likely wreak havoc on cancer, transplant and other immunocompromised patients.

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.

Objectives To determine the effect of age, severity of lung disease, severity and frequency of exacerbation, steroid use, choice of an antibiotic, and the presence of comorbidity on the outcome of treatment for an acute exacerbation of COPD. Design A retrospective chart analysis over 24 months. Setting A university Veterans Affairs medical center. Patients Outpatients with COPD who were treated with an antibiotic over a period of 24 months for an acute exacerbation of COPD. Methods Severity of an acute exacerbation of COPD was defined using the criteria of Anthonisen et al: increased dyspnea, increased sputum volume, and increased sputum purulence. Severity of lung disease was stratified based on FEV 1 percent predicted using American Thoracic Society guidelines (stage I, FEV 1 ≥ 50%; stage II, FEV 1 35 to 49%; stage III, FEV 1 Results One-hundred seven patients with COPD (mean age ± SD, 66.9 ± 9.5 years) experienced 232 exacerbations over 24 months. First-line antibiotics (trimethoprim-sulfamethoxazole, ampicillin/amoxicillin, and erythromycin) were used to treat 78% of all exacerbations. Treatment failure was noted in 12.1% of first exacerbations and 14.7% of all exacerbations, with more than half the failures requiring hospitalization. Host factors that were independently associated with treatment failure included the following: FEV 1 Conclusion The results of our study suggest that patient host factors and not antibiotic choice may determine treatment outcome. Prospective studies in appropriately stratified patients are needed to validate these findings.

The most common adverse effects of the fluoroquinolones involve the gastrointestinal tract, skin and CNS, and are mainly mild and reversible. Of the gastrointestinal events, nausea and vomiting are the most common. Mild hepatic reactions are a class effect, usually presenting as mild transaminase level increases without clinical symptoms. However, postmarketing surveillance has revealed significant hepatotoxicity with trovafloxacin. It is not currently known whether the severe reactions to trovafloxacin are specific to that agent or simply represent an extreme of an emerging class effect. The enormous worldwide usage of, and extensive published adverse effect data on the other fluoroquinolones and naphthyridones suggests the former. In perspective, rare but serious hepatotoxicity has been reported with other fluoroquinolones and the overall incidence of trovafloxacin hepatotoxicity is not dissimilar to that reported with flucloxacillin and amoxicillin-clavulanic acid. CNS reactions vary in severity and include dizziness, convulsions (notably with lomefloxacin) and psychoses. Fluoroquinolones differ in their pro-convulsive activity, relating to their differing potential as gamma-aminobutyric acid antagonists and binding to the N-methyl-D-aspartate receptor. The basis for the increased seizure potential following the coadministration of nonsteroidal anti-inflammatory drugs with certain fluoroquinolones is not fully understood. Fluoroquinolone phototoxicity, caused by the generation of toxic free oxygen species under exposure to UVA radiation, is significantly more common with 8-halogenated compounds. Certain patient groups, e.g. patients with cystic fibrosis, are predisposed to this adverse effect. Murine photocarcinogenicity has been demonstrated with lomefloxacin, but no such effects have been reported in humans. Prolongation of the QTc interval is also a class effect, although cardiac arrhythmias have only been linked with sparfloxacin. Among the newer fluoroquinolones, clinically significant cardiac events are rare or absent but possible interactions in patients receiving other drugs capable of causi ng QT prolongation should be anticipated. Tendinitis and rupture, usually of the Achilles tendon, are rare, class-effects of fluoroquinolones, most frequently reported with pefloxacin. Predisposing factors include aging, corticosteroid use, renal disease, haemodialysis and transplantation. Use of fluoroquinolones in paediatric patients remains contentious. However, accruing human data suggest that restrictions on paediatric use imposed because of fluoroquinolone-induced cartilage damage in juvenile animals, may soon be relaxed. Data from over 1700 children in the UK failed to disclose arthropathy and extensive paediatric use of norfloxacin in Japan and ciprofloxacin in developing countries has been free of articular effects.

In a primary care setting, the efficacy and safety of ciprofloxacin (CIP) 500 mg b.i.d. were compared with those of cefuroxime axetil (CA) 250 mg b.i.d., each given for 10 days, in a nationwide, open, prospective, randomized trial of 1414 adults with acute sinusitis. Patients were enrolled if they had clinically documented acute sinusitis (ie, rhinosinusitis) (

Although controversial, antimicrobial therapy for the treatment of acute exacerbations of chronic bronchitis (AECB) appears beneficial in patients with a history of repeated infections, those who have comorbid illnesses, and those with marked airway obstruction. In a community-based, open, randomized trial, the efficacy and safety of ciprofloxacin (CIP) 750 mg and clarithromycin (CLA) 500 mg, each given twice daily for 10 days, were compared in 2180 patients with AECB (1083 CIP, 1097 CLA). Patients were >40 years of age and had complicated/severe AECB episodes defined as at least three episodes within the past year, at least three comorbid conditions, previous failed antibiotic treatment for AECB within the previous 2 to 4 weeks, or community susceptibility data indicating a high number of resistant pathogens. Significant bacterial isolates (>10(5) colony-forming units per milliliter) from homogenized sputa were identified. Susceptibility to a range of antimicrobials was determined by the microbroth dilution technique. The majority of patients were white (83%) and were current or previous smokers (81%). Mean patient age was 62 years. A history of at least three AECB episodes in the previous year was reported by 54% of CIP-treated patients and 53% of CLA-treated patients. Of 777 primary isolates positively identified and cultured from 673 patients, the bacterial pathogens isolated and their incidence included Haemophilus species, 28%; Moraxella catarrhalis, 18%; Enterobacteriaceae, 18%; Staphylococcus aureus, 17%; Streptococcus pneumoniae, 7%; and Pseudomonas aeruginosa, 4%. Beta-lactamase production was found in 38% of Haemophilus influenzae, 10% of Haemophilus parainfluenzae, and 85% of M catarrhalis isolates. Thirty-four percent of S pneumoniae isolates were resistant to penicillin (minimum inhibitory concentration > or =0.12 mg/L). Among the 673 patients who were valid for clinical assessment and had a pretherapy pathogen isolated, clinical success and overall bacteriologic eradication rates at the end of therapy were 93% and 98% for CIP versus 90% and 96% for CLA. The differences between CIP and CLA did not reach statistical significance. Superinfections were reported significantly more frequently in CLA-treated (3%) versus CIP-treated patients (1%). Eradication rates for specific organisms for CIP and CLA, respectively, were Haemophilus species, 99% and 93%; M catarrhalis, 99% and 100%; S pneumoniae, 91% and 92%; and Enterobacteriaceae, 100% and 95%. Drug-related adverse events occurred in 12% of CIP-treated patients and 10% of CLA-treated patients. CIP 750 mg b.i.d. had a higher (but not statistically significant) clinical and bacteriologic cure rate than CLA 500 mg b.i.d. in the treatment of patients with bacteriologically proven complicated/severe AECB. The causative bacterial pathogens of AECB appear to be evolving, with a predominance of gram-negative and other resistant organisms observed. Thus antibiotic therapy for at-risk patients with AECB should include agents that have activity against gram-negative pathogens.

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...

Antimicrobial therapy has evolved to be an essential component for treating bacterial infection; however, the optimal duration of therapy continues to be defined for a number of different infections. Previously, uncomplicated infections of the lower and upper urinary tracts required treatment durations of 10-14 days and can now be successfully managed with < or = 3-7 days of oral therapy. Similarly, optimal durations of therapy for community-acquired respiratory tract infections continue to be defined with shorter durations being approved, based on the clinical outcome of comparative trials. The shorter durations of therapy are thought to clearly benefit patient care with improved compliance. But, are all of the approved antimicrobial compounds ideal for shorter durations of therapy? Optimal use of these compounds involves re-evaluating each drug's antimicrobial spectrum, pharmacological characteristics, clinical outcome and side-effects profiles, and a reduced likelihood of selecting drug-resistant bacteria during therapy (due to the current environment of global antimicrobial resistance and fewer new antimicrobials under development).

Trained in medical microbiology and infectious diseases in the UK, Glenn Tillotson has over 20 years pharmaceutical experience in various areas, including clinical research, marketing, scientific communications, strategic development and global launch programs. Mainly in the field of anti-infectives, Tillotson has been instrumental in the development of ciprofloxacin and moxifloxacin, as well as other drugs in the Bayer portfolio. After leaving Bayer, he worked as a consultant microbiologist and, in 2003, consulted with Genesoft to help with the commercialization and launch of gemifloxacin, leading to the development of Oscient following the merger of Genesoft and Genome Therapeutics. From late 2003 to early 2006, he focused his efforts on the launch of gemifloxacin into US clinical practice, as well as comarketing and business development deals globally. In April 2006, Tillotson joined Replidyne Inc. as Executive Director of Scientific Affairs working on faropenem, REP 8839 and REP 3123. Presently, Tillotson is Head of Medical Affairs at ViroPharma Inc., where he oversees educational, publication and other related activities for Vancocin(®), maribavir and Cinryze™. Most recently, Tillotson was a member of the Scientific Steering Committee for the International Society of Chemotherapy's Symposium on Clostridium difficile in Leipzig, Germany. Here, he talks with Expert Review of Clinical Pharmacology about the challenge of antibiotic resistance from an industry perspective.

Multidrug-resistant bacteria are becoming more common and due to their multiplicity of mechanisms, they are frequently resistant to many if not all of the current antibiotics. This daunting spectre has been the target of many research efforts into conventional antibiotics and alternative approaches. This review focuses on the more recent advances in these fields with an overview on peptidomimetics, nanoparticles and their derivatives, FimH inhibitors, quorum sensing inhibition molecules, neoglycosides and phage therapies. These various approaches are at different stages of development, some are closer to the clinic than others, but recent regulatory guidance and re-awakened interest from the pharmaceutical companies gives us some optimism for the future.

In a multicenter, community-based study involving more than 300 primary care physicians in the United States, the efficacy and safety of ciprofloxacin and clarithromycin were compared in the treatment of patients with complicated or severe acute bacterial exacerbations of chronic bronchitis (i.e., those who had failed previous antibiotic treatment within the prior 2 to 4 weeks; those with susceptibility data suggestive of a resistant pathogen; those having three or more acute exacerbations of chronic bronchitis [AECB] within the past year; and those having three or more comorbid conditions). Patients were randomized to either ciprofloxacin (CIP) 750 mg BID or clarithromycin (CLR) 500 mg BID, both administered for 10 days; all patients were treated on an outpatient basis. Clinical response at the end of therapy was the primary efficacy variable. An interim analysis was performed on the results from 743 patients (369 CIP, 374 CLR) with clinical and bacteriologic evidence of a bronchopulmonary infection who had completed an ongoing study as of the end of May 1997. Three hundred nine pathogens were isolated before therapy, including Haemophilus spp (75 isolates), Moraxella catarrhalis (67 isolates), Staphylococcus aureus (55 isolates), and Streptococcus pneumoniae (23 isolates). Seven hundred eighteen patients (97%) were included in the efficacy-valid population. Clinical success at the end of therapy was observed in 90% (272 of 302) and 88% (274 of 313) of efficacy-valid patients treated with CIP and CLR, respectively (95% confidence interval [CI] = -2.4 to 7.6). Corresponding rates for the intent-to-treat population were also 90% (283 of 314) and 88% (281 of 321), respectively (95% CI = -2.3 to 7.5). The bacteriologic response for efficacy-valid patients at the end of therapy was 98% (119 of 122) for CIP-treated and 93% (103 of 111) for CLR-treated patients (95% CI = -0.8 to 10.2). The eradication rates for the three most commonly isolated gram-negative pathogens were 100% for CIP-treated and 95% for CLR-treated patients and 96% each for the two most commonly isolated gram-positive organisms. Superinfections due to respiratory tract pathogens were more common in the CLR group (10 organisms) than in the CIP group (4 organisms). Seventy-four (20%) CIP-treated and 62 (17%) CLR-treated patients reported 118 and 103 respective study-emergent adverse events. Headache, abdominal pain, diarrhea, nausea, and vomiting in CIP-treated patients and diarrhea, nausea, vomiting, and taste perversion in CLR-treated patients were the most commonly reported adverse events. Treatment of patients with complicated or severe AECB with CIP 750 mg BID was associated with rates of clinical success and bacteriologic eradication similar to those with CLR.

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.