John H. Powers

Fluoroquinolone-Resistant Campylobacter Species and the Withdrawal of Fluoroquinolones from Use in Poultry: A Public Health Success Story

Campylobacter species cause 1.4 million infections each year in the United States. Fluoroquinolones (e.g., ciprofloxacin) are commonly used in adults with Campylobacter infection and other infections. Fluoroquinolones (e.g., enrofloxacin) are also used in veterinary medicine. Human infections with fluoroquinolone-resistant Campylobacter species have become increasingly common and are associated with consumption of poultry. These findings, along with other data, prompted the US Food and Drug Administration to propose the withdrawal of fluoroquinolone use in poultry in 2000. A lengthy legal hearing concluded with an order to withdraw enrofloxacin from use in poultry (effective in September 2005). Clinicians are likely to continue to encounter patients with fluoroquinolone-resistant Campylobacter infection and other enteric infection because of the continued circulation of fluoroquinolone-resistant Campylobacter species in poultry flocks and in persons returning from foreign travel who have acquired a fluoroquinolone-resistant enteric infection while abroad. Judicious use of fluoroquinolones and other antimicrobial agents in human and veterinary medicine is essential to preserve the efficacy of these important chemotherapeutic agents.

Discovery research: the scientific challenge of finding new antibiotics

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.

Standardizing measurement of chronic obstructive pulmonary disease exacerbations. Reliability and validity of a patient-reported diary.

RATIONALE Although exacerbations are an important problem in chronic obstructive pulmonary disease (COPD) and a target of intervention, there is no valid, standardized tool for assessing their frequency, severity, and duration. OBJECTIVES This study tested the properties of the Exacerbations of Chronic Pulmonary Disease Tool (EXACT), a new patient-reported outcome diary. METHODS A prospective, two-group, observational study was conducted in patients with COPD. The acute group (n = 222) was enrolled during a clinic visit for exacerbation with follow-up visits on Days 10, 29, and 60. The stable group (n = 188), recruited by telephone or during routine visits, was exacerbation free for at least 60 days. MEASUREMENTS AND MAIN RESULTS Acute patients completed the diary on Days 1-29 and 60-67; stable patients for 7 days. All patients provided stable-state spirometry and completed the St. George Respiratory Questionnaire-COPD (SGRQ-C). Acute patient assessments included clinician and patient global ratings of exacerbation severity and recovery. Mean age of the sample (n = 410) was 65 (± 10) years; 48% were male; stable FEV₁ was 51% predicted (± 20). Internal consistency (Pearson separation index) for the EXACT was 0.92, 1-week reproducibility (stable patients; intraclass correlation) was 0.77. EXACT scores correlated with SGRQ-C (r = 0.64; P < 0.0001) and differentiated acute and stable patients (P < 0.0001). In acute patients, scores improved over time (P < 0.0001) and differentiated between degrees of clinician-rated exacerbation severity (P < 0.05). EXACT change scores differentiated responders and nonresponders on Day 10, as judged by clinicians or patients (P < 0.0001). CONCLUSIONS Results suggest the EXACT is reliable, valid, and sensitive to change with exacerbation recovery.

Development of the EXAcerbations of Chronic Obstructive Pulmonary Disease Tool (EXACT): a patient-reported outcome (PRO) measure.

BACKGROUND This article describes the qualitative methods used to develop the EXAcerbation of Chronic Pulmonary Disease Tool (EXACT), a new patient-reported outcome (PRO) instrument for evaluating frequency, severity, and duration of exacerbations of chronic obstructive pulmonary disease (COPD). METHODS Focus groups and interviews were conducted in the United States with COPD patients treated for exacerbations during the past 6 months. Participants were asked to describe exacerbation attributes, care-seeking cues, and indications of progression and recovery. An iterative process was used to identify themes in the data to inform instrument content and structure. Cognitive debriefing interviews were performed to evaluate and revise the draft item pool. Experts in COPD, instrument development, and clinical research participated in the process. RESULTS Eighty-three subjects participated in elicitation focus groups or interviews (n=48); elicitation interviews with cognitive debriefing (n=23), or cognitive interviews alone (n=12). Mean age of the sample was 65 years (SD=10); 45% were male; mean FEV-1% predicted was 44% (SD=16). Participants characterized exacerbations as a persistent increase in the severity of respiratory symptoms and other systemic manifestations accompanied by a dramatic reduction in activity. Specific attributes included shortness of breath, chest congestion, cough, sputum, chest discomfort, feeling weak or tired, sleep disturbances, and concern or worry. The diary card of 23 candidate items was debriefed in booklet and electronic format. CONCLUSIONS Qualitative data from patients and input from experts formed the basis of the EXACTs structure and item pool, ready for empirically based item reduction and reliability and validity testing.

Anti-infective research and development—problems, challenges, and solutions

In communities and hospitals around the world, the number of patients with antibiotic-resistant infections continues to climb. Our current armamentarium of drugs are gradually becoming ineffective and a new pipeline of robust compounds is needed urgently. In this Forum, we present several perspectives on the problems and pitfalls of drug discovery and development, the challenges faced by the practising physician, and potential solutions to protecting and safeguarding the public health of future generations.

The urgent need for new antibacterial agents

I find it continually amazing that society as a whole does not recognize the consequences of rising antimicrobial resistance as the threat it most certainly is. This is not for a lack of sustained activity by those who share these concerns. Far from it. Since 1997 there have been a plethora of enquiries, reports and recommendations—many from important bodies in both Europe and North America, yet little meaningful action has materialized. Some might consider this to be rather negative and an overstatement, yet can they point out a concrete outcome to all this activity? I like to think that the UK has led the way in raising concerns that antibiotic use, especially overuse (in animals as well as man) will hasten the day when these essential agents will lose their efficacy. The Swann Committee first brought this to our attention in 1969, and in 1998 a House of Lords report starkly stated that antimicrobial resistance was a ‘major threat to public health’. Most recently, the Infectious Diseases Society of America (IDSA) and the European Union, among others, have voiced their concerns. In 2009 the WHO called antibiotic resistance one of the three greatest threats to human health, and in 2011 the focus of World Health Day was ‘Combating Antibiotic Resistance’. However, antimicrobial resistance moves on in an inexorable fashion and the prospects for new agents are as bleak as ever. Perhaps it is us, the health professionals, who are at fault, either in the nature of our message, or in approaching the wrong groups who cannot influence outcomes? The BSAC has changed tack in its report on ‘The Urgent Need’, as outlined in the articles accompanying this one. – 9 Rather than restate the concerns surrounding antimicrobial resistance, its surveillance and how it might be contained (or more accurately, how its progress might be slowed), the BSAC adopted a different approach, focusing on the barriers to discovery and development of new technologies that might combat resistance (including new antimicrobial agents) and how these might be overcome. The Working Party of the BSAC examined three areas, namely research, regulation and economics. While recognizing that these areas are not distinct and there is much important overlap, the Working Party was challenged to suggest a practical framework for action. Critically there was an awareness on the part of the Working Party that the BSAC cannot undertake this immense task on its own, and co-operation with others is key. I do not wish to précis the report here, but rather make some personal comments on what I consider to be a few important areas. In research there is a major concern that international expertise in natural product discovery is being rapidly lost—how long has it been since such an antibacterial compound has been marketed? Overoptimism in genomics and highthroughput screening as the answer to the discovery of new agents in the 1990s would appear to have put back the cause by at least a decade. Research into how to influence the public’s perceptions of the risks confronting them (hence the political response) is also needed. Most certainly the regulatory issues relating to the licensing of new antimicrobials are extremely important. The bureaucrats are risk averse, yet do not take account of the risks to society of their inaction. This would change if political concerns were more loudly voiced. It is my personal opinion that it is changes in the economic field that are most likely to yield results. We were not the first to expound the economic arguments. Everything the Working Party heard from industry makes me believe that the marketplace must change. A course of antibiotics costs a few pounds or dollars and can save lives. In hospital practice we shudder if the costs rise into the hundreds. The angiogenesis inhibitor bevacizumab (trade name Avastin) is one of the most expensive widely marketed drugs. In 2008 sales generated nearly US

Desirability of Outcome Ranking (DOOR) and Response Adjusted for Duration of Antibiotic Risk (RADAR)

2.7 billion for Genentech, yet it has only modest effects on patient survival in a number of cancers. This is not to say it should not be used, but rather that there should be a rebalancing of risks and, more importantly, benefits. I would suggest that antimicrobials (other than a few antifungals) should be at a higher premium. Antimicrobial development must allow pharmaceutical companies realistic returns on their investment. This is crucial if society is to obtain new agents. So what actions should the BSAC undertake? The Working Party has suggested a number of short-, mediumand long-term activities. These, realistically, revolve around communication, in its broadest sense, with clinicians and academics, but possibly more importantly, with opinion formers in the UK and further afield. Such a programme of work, which will not be cheap, should include other parties and could usefully include the participation of the pharmaceutical industry.

Evaluation of Antihemagglutinin and Antineuraminidase Antibodies as Correlates of Protection in an Influenza A/H1N1 Virus Healthy Human Challenge Model

Clinical trials that compare strategies to optimize antibiotic use are of critical importance but are limited by competing risks that distort outcome interpretation, complexities of noninferiority trials, large sample sizes, and inadequate evaluation of benefits and harms at the patient level. The Antibacterial Resistance Leadership Group strives to overcome these challenges through innovative trial design. Response adjusted for duration of antibiotic risk (RADAR) is a novel methodology utilizing a superiority design and a 2-step process: (1) categorizing patients into an overall clinical outcome (based on benefits and harms), and (2) ranking patients with respect to a desirability of outcome ranking (DOOR). DOORs are constructed by assigning higher ranks to patients with (1) better overall clinical outcomes and (2) shorter durations of antibiotic use for similar overall clinical outcomes. DOOR distributions are compared between antibiotic use strategies. The probability that a randomly selected patient will have a better DOOR if assigned to the new strategy is estimated. DOOR/RADAR represents a new paradigm in assessing the risks and benefits of new strategies to optimize antibiotic use.

Clinical Outcome Assessments: Conceptual Foundation—Report of the ISPOR Clinical Outcomes Assessment - Emerging Good Practices for Outcomes Research Task Force

ABSTRACT Despite long-term investment, influenza continues to be a significant worldwide problem. The cornerstone of protection remains vaccination, and approved vaccines seek to elicit a hemagglutination inhibition (HAI) titer of ≥1:40 as the primary correlate of protection. However, recent poor vaccine performance raises questions regarding the protection afforded and whether other correlates of protection should be targeted. A healthy volunteer challenge study was performed with a wild-type 2009 A(H1N1)pdm influenza A challenge virus at the NIH Clinical Center to evaluate two groups of participants with HAI titers of ≥1:40 and <1:40. The primary objective was to determine whether participants with HAI titers of ≥1:40 were less likely to develop mild to moderate influenza disease (MMID) after intranasal inoculation. HAI titers of ≥1:40 were protective against MMID but did not reduce the incidence of symptoms alone. Although the baseline HAI titer correlated with some reduction in disease severity measures, overall, the baseline NAI titer correlated more significantly with all disease severity metrics and had a stronger independent effect on outcome. This study demonstrates the importance of examining other immunological correlates of protection rather than solely HAI titers. This challenge study confirms the importance of NAI titer as a correlate and for the first time establishes that it can be an independent predictor of reduction of all aspects of influenza disease. This suggests that NAI titer may play a more significant role than previously thought and that neuraminidase immunity should be considered when studying susceptibility after vaccination and as a critical target in future influenza vaccine platforms. IMPORTANCE This study represents the first time the current gold standard for evaluating influenza vaccines as set by the U.S. Food and Drug Administration and the European Medicines Agency Committee for Medicinal Products for Human Use, a “protective” hemagglutination inhibition (HAI) titer of ≥1:40, has been evaluated in a well-controlled healthy volunteer challenge study since the cutoff was established. We used our established wild-type influenza A healthy volunteer human challenge model to evaluate how well this antibody titer predicts a reduction in influenza virus-induced disease. We demonstrate that although higher HAI titer is predictive of some protection, there is stronger evidence to suggest that neuraminidase inhibition (NAI) titer is more predictive of protection and reduced disease. This is the first time NAI titer has been clearly identified in a controlled trial of this type to be an independent predictor of a reduction in all aspects of influenza. This study represents the first time the current gold standard for evaluating influenza vaccines as set by the U.S. Food and Drug Administration and the European Medicines Agency Committee for Medicinal Products for Human Use, a “protective” hemagglutination inhibition (HAI) titer of ≥1:40, has been evaluated in a well-controlled healthy volunteer challenge study since the cutoff was established. We used our established wild-type influenza A healthy volunteer human challenge model to evaluate how well this antibody titer predicts a reduction in influenza virus-induced disease. We demonstrate that although higher HAI titer is predictive of some protection, there is stronger evidence to suggest that neuraminidase inhibition (NAI) titer is more predictive of protection and reduced disease. This is the first time NAI titer has been clearly identified in a controlled trial of this type to be an independent predictor of a reduction in all aspects of influenza.

Repairing the Broken Market for Antibiotic Innovation

An outcome assessment, the patient assessment used in an endpoint, is the measuring instrument that provides a rating or score (categorical or continuous) that is intended to represent some aspect of the patients health status. Outcome assessments are used to define efficacy endpoints when developing a therapy for a disease or condition. Most efficacy endpoints are based on specified clinical assessments of patients. When clinical assessments are used as clinical trial outcomes, they are called clinical outcome assessments (COAs). COAs include any assessment that may be influenced by human choices, judgment, or motivation. COAs must be well-defined and possess adequate measurement properties to demonstrate (directly or indirectly) the benefits of a treatment. In contrast, a biomarker assessment is one that is subject to little, if any, patient motivational or rater judgmental influence. This is the first of two reports by the ISPOR Clinical Outcomes Assessment - Emerging Good Practices for Outcomes Research Task Force. This report provides foundational definitions important for an understanding of COA measurement principles. The foundation provided in this report includes what it means to demonstrate a beneficial effect, how assessments of patients relate to the objective of showing a treatments benefit, and how these assessments are used in clinical trial endpoints. In addition, this report describes intrinsic attributes of patient assessments and clinical trial factors that can affect the properties of the measurements. These factors should be considered when developing or refining assessments. These considerations will aid investigators designing trials in their choice of using an existing assessment or developing a new outcome assessment. Although the focus of this report is on the development of a new COA to define endpoints in a clinical trial, these principles may be applied more generally. A critical element in appraising or developing a COA is to describe the treatments intended benefit as an effect on a clearly identified aspect of how a patient feels or functions. This aspect must have importance to the patient and be part of the patients typical life. This meaningful health aspect can be measured directly or measured indirectly when it is impractical to evaluate it directly or when it is difficult to measure. For indirect measurement, a concept of interest (COI) can be identified. The COI must be related to how a patient feels or functions. Procedures are then developed to measure the COI. The relationship of these measurements with how a patient feels or functions in the intended setting and manner of use of the COA (the context of use) could then be defined. A COA has identifiable attributes or characteristics that affect the measurement properties of the COA when used in endpoints. One of these features is whether judgment can influence the measurement, and if so, whose judgment. This attribute defines four categories of COAs: patient reported outcomes, clinician reported outcomes, observer reported outcomes, and performance outcomes. A full description as well as explanation of other important COA features is included in this report. The information in this report should aid in the development, refinement, and standardization of COAs, and, ultimately, improve their measurement properties.