Valuing antibiotics: The role of the hospital clinician.

The global public health threat of antibiotic-resistant infections as well as the lack of new treatments in clinical development is a critical issue. Reasons for this include diminished commercial incentives for pharmaceutical companies to develop new antibiotics, which part-reflects a shift in antibiotic marketing paradigm from broad deployment to targeted therapy in relatively small patient populations. Such changes are encouraged by antimicrobial stewardship (AMS). Other factors include a lack of recognition in the traditional assessment of new antibiotics by regulators, health technology assessors and payers of the broad range of benefits of new agents, particularly their value to health care, economies and society. Recognising the seriousness of the situation, there have been recent changes and proposals by regulators for modification of the assessment process to accommodate a broader range of acceptable data supporting new drug applications. There is also increasing recognition by some payers of the societal benefit of new antibiotics and the need for financial incentives for those developing high-priority antibiotics. However, progress is slow, with recent publications focusing on industry and strategic perspectives rather than clinical implications. In this opinion piece, we therefore focus on clinicians and the practical steps they can take to drive and contribute to increasing awareness and understanding of the value of antibiotics. This includes identifying and gathering appropriate alternative data sources, educating on AMS and prescribing habits, and contributing to international antibiotic susceptibility surveillance models.

De-escalation from micafungin is a cost-effective alternative to traditional escalation from fluconazole in the treatment of patients with systemic Candida infections.

BACKGROUND: Systemic Candida infections (SCI) occur predominantly in intensive care unit patients and are a common cause of morbidity and mortality. Recently, changes in Candida epidemiology with an increasing prevalence of SCI caused by Candida non-albicans species have been reported. Resistance to fluconazole and azoles in general is not uncommon for non-albicans species. Despite guidelines recommending initial treatment with broad-spectrum antifungals such as echinocandins with subsequent switch to fluconazole if isolates are sensitive (de-escalation strategy), fluconazole is still the preferred first-line antifungal (escalation) in many clinical practice settings. After diagnosis of the pathogen, the initial therapy with fluconazole is switched to a broad-spectrum antifungal if a non-albicans is identified. METHODS: The cost-effectiveness of initial treatment with micafungin (de-escalation) vs fluconazole (escalation) in patients with SCI was estimated using decision analysis based on clinical and microbiological data from pertinent studies. The model horizon was 42 days, and was extrapolated to cover a lifetime horizon. All costs were analyzed from the UK NHS perspective. Several assumptions were taken to address uncertainties; the limitations of these assumptions are discussed in the article. RESULTS: In patients with fluconazole-resistant isolates, initial treatment with micafungin avoids 30% more deaths and successfully treats 23% more patients than initial treatment with fluconazole, with cost savings of £1621 per treated patient. In the overall SCI population, de-escalation results in 1.2% fewer deaths at a marginal cost of £740 per patient. Over a lifetime horizon, the incremental cost-effectiveness of de-escalation vs escalation was £15,522 per life-year and £25,673 per QALY. CONCLUSIONS: De-escalation from micafungin may improve clinical outcomes and overall survival, particularly among patients with fluconazole-resistant Candida strains. De-escalation from initial treatment with micafungin is a cost-effective alternative to escalation from a UK NHS perspective, with a differential cost per QALY below the 'willingness-to-pay' threshold of £30,000.

Epidemiology, microbiology, and treatment considerations for bacterial pneumonia complicating influenza.

Post-influenza bacterial pneumonia is a major cause of morbidity and mortality associated with both seasonal and pandemic influenza virus illness. However, despite much interest in influenza and its complications in recent years, good clinical trial data to inform clinicians in their assessment of treatment options are scant. This paucity of evidence needs to be addressed urgently in order to improve guidance on the management of post-influenza bacterial pneumonia. The objectives of the current article are to evaluate the emergence of the 2009 H1N1 influenza pandemic and use this information as background for an in-depth review of the epidemiology of bacterial pneumonia complicating influenza, to review the bacterial pathogens most likely to be associated with post-influenza bacterial pneumonia, and to discuss treatment considerations in these patients. When determining optimal management approaches, both antiviral and antibacterial agents should be considered, and their selection should be based upon a clear understanding of how their mechanisms of action intervene in the pathogenesis of post-influenza acute bacterial pneumonia.

Antibiotic de-escalation.

Antibiotic de-escalation is a mechanism whereby the provision of effective initial antibiotic treatment is achieved while avoiding unnecessary antibiotic use that would promote the development of resistance. It is a key element within antimicrobial stewardship programs and treatment paradigms for serious sepsis. The embodiment of de-escalation is that based on microbiology results around the day 3 therapy point; the empiric antibiotic(s) that were started are stopped or reduced in number and/or narrowed in spectrum. Data are presented here which demonstrate that de-escalation is clinically effective and appropriate. However, the need for further studies, particularly in terms of realization of full benefits as well as implementation tools, is highlighted. De-escalation ought now to form a part of routine antimicrobial management, though how best to do it and the full breadth and scope of benefits remain to be identified.

Antibiotic heterogeneity.

In modern sepsis management, long-held concerns about the inexorable rise of antimicrobial resistance have led to a key focus on antibiotic stewardship. Among the many strands that come together to provide a complete picture of stewardship is the issue of how antibiotic classes are deployed. Based on consistent results from mathematical modelling studies, the concept of a structured approach to such class use has evolved over the last decade. Whereas antibiotic cycling was initially perceived to be the strongest candidate for investigation in this field, over recent years the focus has shifted to antibiotic heterogeneity. Although there is presently little clinical work available on antibiotic heterogeneity, the available data demonstrate that this is an attractive option for enabling clinicians to make the most of their existing pool of antimicrobial classes by holding at bay, as much as possible, the emergence of resistance.

Approaches to improving antibiotic management.

New information is available to improve antibiotic outcomes in severe sepsis where increasing resistance and reducing novel compound development make reaching the right decisions ever more difficult and important.

The new treatment paradigm and the role of carbapenems.

The global increase in antibiotic resistance is promoted by the widespread use of broad-spectrum antibiotics, creating a continuous selective pressure on bacteria. This resistance is depleting the number of effective antimicrobial agents. Since there have been few new agents active against Gram-negative bacteria in particular developed over the last two decades, it is important to make the most of existing antibiotics. Therefore, rational use of antimicrobial agents is vital in establishing a successful strategy to control and prevent both the clinical impact and the development of further resistance. Careful selection of the appropriate antimicrobial agent combined with correct dosing, duration of treatment and route of administration are all important to the success of this strategy and need to be coupled with antimicrobial resistance surveillance. Progress against the treatment strategy approach for optimising clinical outcomes whilst preventing antibacterial resistance based on antibiotic de-escalation will be reviewed with particular emphasis on the role of the carbapenems. This approach attempts to balance the need to provide appropriate initial treatment whilst limiting the emergence of antibacterial resistance.

Guidelines for UK practice for the diagnosis and management of methicillin-resistant Staphylococcus aureus (MRSA) infections presenting in the community.

These guidelines have been developed by a Working Party convened on behalf of the British Society for Antimicrobial Chemotherapy. Their aim is to provide general practitioners and other community- and hospital-based healthcare professionals with pragmatic advice about when to suspect MRSA infection in the community, when and what cultures should be performed and what should be the management options, including the need for hospitalization.

Improving practice--the Hospital Pharmacy Initiative revisited.

The Hospital Pharmacy Initiative was a 12 million pounds sterling scheme introduced in England in 2003 and aimed at improving antimicrobial prescribing. Although significant successes have been claimed for the scheme, there is evidence which demonstrates that the untargeted and essentially undirected investment where no clear objectives were set has resulted in extremely variable developments with arguably minimal gains attributable to the programme. This contrasts strongly with the Scottish approach where form and function has been detailed with a focus on service sustainability in the ongoing challenge of improving prudent antimicrobial prescribing.

Trends in antimicrobial susceptibility in UK centres: the MYSTIC Programme (1997-2002).

Trends in antimicrobial susceptibilities in three UK centres participating in the MYSTIC Programme were examined from 1997 to 2002. Isolates were tested using standard methodology to determine the susceptibility breakpoints of meropenem and several other antimicrobial agents including imipenem, ceftazidime, piperacillin/tazobactam, ciprofloxacin and gentamicin. Data are grouped in 2-year blocks. The carbapenems were the most active agents tested against the Enterobacteriaceae (99-100% and 98-100% susceptibility to meropenem and imipenem, respectively) and non-fermenters, including Pseudomonas spp. and Acinetobacter spp. With the exception of susceptibility to ciprofloxacin, which decreased among Enterobacteriaceae at the end of the 6-year period, all antibiotics tested retained their levels of activity. The proportion of extended-spectrum beta-lactamase (ESBL)- and AmpC-producing Enterobacteriaceae increased during the study (4.8% and 11.3% in 1997-1998; 7.4% and 16.7% in 2001-2002, respectively). Both meropenem and imipenem retained their potency against these ESBL- and AmpC-producing isolates (100% for all time periods). All the other antimicrobial agents tested had much lower susceptibility against these resistant isolates and this decreased further over the 6-year period, with the exception of tazobactam, which maintained its low levels. Although all antibiotics tested retained acceptable activity, the carbapenems remained the most active antimicrobial agents against Gram-negative bacteria, including ESBL- and AmpC-producing isolates.

The OPTAMA programme: utilizing MYSTIC (2002) to predict critical pharmacodynamic target attainment against nosocomial pathogens in Europe.

OBJECTIVES: The Optimising Pharmacodynamic Target Attainment using the MYSTIC (Meropenem Yearly Susceptibility Test Information Collection) Antibiogram (OPTAMA) programme identifies antibiotic regimens with the highest probability of attaining critical pharmacodynamic targets, accounting for the inherent variability in pharmacokinetics, dosages and MIC distributions. METHODS: European MIC data were obtained from the MYSTIC programme. Pharmacodynamic target attainment was calculated by Monte Carlo simulation for meropenem, imipenem, ceftazidime, cefepime, piperacillin/tazobactam and ciprofloxacin against Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa. RESULTS: Significant differences in probability of target attainment were found, with Northern Europe demonstrating the highest probabilities of target attainment and Eastern Europe the lowest. The carbapenems had the highest target attainments and susceptibility levels across all regions and pathogens. The cephalosporins demonstrated high target attainments and susceptibility results against E. coli and K. pneumoniae in Northern and Southern Europe. Piperacillin/tazobactam and ciprofloxacin had the lowest levels for both parameters in all regions. Desirable target attainment was not achieved (except for carbapenems in Northern Europe) for A. baumannii and P. aeruginosa; thus, combination therapy may be appropriate empirical therapy for these pathogens in Southern and Eastern Europe. The closest correlations between target attainment and susceptibility were for meropenem 1 g every 8 h, imipenem 0.5 g every 6 h and ceftazidime 1 g every 8 h. CONCLUSIONS: The study highlighted significant overestimations between the probability of target attainment and the reported percentage susceptibility, particularly for piperacillin/tazobactam and ciprofloxacin. The approach of the OPTAMA programme provides a novel tool which complements susceptibility data to help in the selection of appropriate empirical antibiotic therapy.

Antibiotic cycling: more than it might seem?

In the present battle against the rising tide of resistance, several interventions have been proposed to help control the situation. One of these is a process of planned antibiotic restriction, introduced through cycling drug selection based on local surveillance. Although such antibiotic cycling has been the subject of much discussion for 20 years, there are relatively few data available to assess its worth. A recent systematic review found only four studies worthy of inclusion and concluded that antibiotic cycling could not, at present, be promoted as a methodology to control resistance. This paper considers the complete literature and through demonstrating consistent benefits across the breadth and depth of the findings, suggests that whereas further work is required, nevertheless antibiotic cycling-as part of a suite of control measures-is a valid option.