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Highlights from a satellite symposium at the 7th Western Pacific Congress of Chemotherapy and Infectious Diseases: Advanced Strategies for Evaluation and Medical Management of Lower Respiratory Tract Infections
Hong Kong, China, December 12, 2000

CONTENTS

Introduction

CAP - Improved Diagnosis Results in Improved Care

The Problem of Patients Who Fail Initial Therapy

Optimal Treatment of High Risk CAP patients

Rational Approach for the Management of AECB/COPD

How to Manage Patients with COPD Who Fail Initial Therapy

Optimal Treatment of AECB High-Risk Patients

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Introduction

A satellite symposium held as part of the 7th Western Pacific Congress of Chemotherapy and Infectious Diseases provided a much-requested forum in which real, practical issues relating to management of lower respiratory tract infections (LRTIs) could be discussed. A group of world renown experts were brought together to present the latest thoughts on the optimal diagnosis and treatment of patients with community-acquired pneumonia (CAP) and acute exacerbations of chronic bronchitis (AECB). The Chairman, Professor Wah Kit Lam, Division of Respiratory and Critical Care Medicine, University of Hong Kong, Hong Kong, China, began the session by noting that these are exceedingly important diseases in terms of morbidity and mortality, with substantial costs for both the individual and the wider community. Therefore, it is very clear that there is a need for strategies aimed at optimising the care of these patients, particularly those at high risk such as elderly and subjects in chronic-care facilities or with coexisting health problems. The following summarises the most important points presented by this panel of distinguished speakers.
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CAP - Improved Diagnosis Results in Improved Care

Professor Michael J. Fine, Division of General Internal Medicine, University of Pittsburgh, Pittsburgh, PA, USA, provided an algorithmic approach to the diagnosis and risk stratification of patients with CAP. He stressed that before finalising a diagnosis of CAP, it is important that the physician consider other possible causes of the patients' symptoms. Thus, the full differential diagnosis needs to be considered. In addition, to confirm the diagnosis of CAP, a pulmonary infiltrate needs to be evident on the chest radiograph.

Once the diagnosis is confirmed, the physician then needs to decide on the most appropriate site of care for the individual patient. This is of increasing relevance at the present time, with ways of improving cost effectiveness of treatment undergoing increased assessment. The need for guidelines clarifying which patients should be hospitalised is highlighted by the fact that treatment of inpatients is twenty times higher than that for patients who are not hospitalised.

With this in mind, the Pneumonia Patient Outcomes Research Team (PORT) project developed a clinically applicable prediction rule for short-term mortality outcomes in patients with CAP. Eleven variables were identified as independently associated with short-term mortality, and a further seven variables also used to develop a risk score (Table 1).

Table 1. Computation of risk score by using the PORT prediction rule
Table1

Patients are given a total score based on whether these variables are present. Thus, a 55-year-old man with congestive heart failure, fever, and an increased respiratory rate would have a score of 100, and be classified as risk group IV. Each risk group profile is shown in Table 2, with the mortality associated with each group assessed by three different studies. This illustrates the rapid rise in mortality from less than 1% for groups I-III, jumping to 9.3% for group IV, and 27% for group V. To improve overall mortality rates, physicians should target these patients. Using these data, Dr. Fine recommended that low-risk patients (classes I-III) should be treated at home. By using the PORT prediction rule, it is possible to improve the management of patients with CAP, and its use has been recommended by the most recent guidelines published by the Infectious Diseases Society of America (ISDA).

Table 2. Comparison of risk class-specific mortality from various studies

Table2
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The Problem of Patients Who Fail Initial Therapy

The question then turned to how best to manage those patients who do not respond to initial treatment. This issue was discussed by Professor Thomas M. File Jr., Department of Internal Medicine, Northeastern Ohio Universities College of Medicine, Rootstown, OH, USA, who noted that in this situation the physician must first confirm that the correct diagnosis was made, and if this is confirmed, attention then needs to turn to other factors. These include pathogen-related issues (unusual or resistant pathogens); host-related issues such as an empyema or a drug-related problem where the wrong antimicrobial was prescribed or the wrong dose was administered. Thus, the physician needs to identify the causative pathogen and confirm its susceptibility to specific agents. The most common causes of CAP can change depending on the severity of illness (Table 3).

Table 3. Etiology of CAP - Most common causesa
Table3

When such confirmatory tests are unable to be done, agents such as levofloxacin should be prescribed, which covers a wide spectrum of pathogens including atypicals and resistant organisms. A recent study of treatment failures of hospitalised CAP patients found the most likely cause was resistant pathogens, with Streptococcus pneumoniae the most often implicated. If the steps suggested earlier are followed, those patients who do not respond to initial empiric antimicrobial therapy have the greatest likelihood of achieving a good final outcome.

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Optimal Treatment of High Risk CAP patients

Another area of specific concern in managing CAP patients is the subgroup of high-risk patients. By identifying such patients as early as possible, the physician is able to improve their outcomes. Professor Claude Carbon, Internal Medicine Unit, Bichat-Claude Bernard Hospital, Paris, France, documented the four most important factors predisposing to severe CAP as chronic obstructive pulmonary disease (COPD), chronic heart disease, diabetes, and a high alcohol intake. Age is another important predisposing factor, with those patients older than 60 years at greater risk of developing serious CAP. Identification of these patients allows therapeutic strategies that will be more likely to result in a good clinical outcome. Guidelines recently published by IDSA, Canadian Infectious Disease Society (CIDS), and Canadian Thoracic Society (CTS) have recommended the use of respiratory fluoroquinolones as a first-line choice for outpatients with modifying factors, nursing home residents, and hospitalised patients in medical wards. This recommendation is gaining even greater acceptance with recent results from an investigation into initial therapy and mortality showing that a fluoroquinolone alone was able to significantly decrease the risk of mortality by day 30, compared to a second- or third-generation cephalosporin plus a macrolide. Fluoroquinolones, as a class, continue to increase in use in managing RTIs, with excellent clinical results published for levofloxacin, one of the newer respiratory fluoroquinolones available.
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Rational Approach for the Management of AECB/COPD

The symposium then turned to the common problem of AECB or acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Associate Professor Kenneth W.T. Tsang, Division of Respiratory and Critical Care Medicine, The University of Hong Kong, Hong Kong, China, began the session by commenting that these infections present with extremely common symptoms of dyspnoea, chest pain, and increasing sputum production, making it important for the physician to carefully consider the differential diagnosis before confirming a diagnosis of AECB (table 4)

Table 4. Differential diagnoses for acute exacerbation of COPD
Table4

Other conditions that need to be considered include asthma, which can coexist with COPD. Bronchiectasis, which is common in Asia, often presents with chronic sputum production and exacerbations, and may be the underlying disease in many COPD patients. Tuberculosis, described as the most important infectious disease in the world, also needs to be ruled out. Other disorders that need to be included in the differential diagnosis are cystic fibrosis, sinusitis, upper respiratory sepsis, and diffuse panbronchiolitis, particularly in Japanese patients. In addition, melioidosis, a suppurative disease endemic in parts of Southeast Asia, lung abscess, pneumonia, and lung cancer need to be considered. Finally, gastro-oesophageal reflux, or a foreign body in the airway, can present with symptoms similar to those of AECB and needs to be ruled out.
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How to Manage Patients with COPD Who Fail Initial Therapy

Recent research into optimal management of AECOPD was reported by Professor Michael P. Habib, Pulmonary Section, Veterans Affairs Medical Center, Tucson, USA, who noted that 35 days after treatment only 75% of patients had returned to their baseline peak flow levels, while 5% never returned to baseline scores. As with the CAP patients, it is important to confirm the diagnosis of AECB or AECOPD in those patients who fail initial therapy. Once this is confirmed, there is a need to optimise therapy. This includes introducing bronchodilators and a short course of corticosteroids, which have been shown to be beneficial for at least 6 months after the exacerbation.

One major cause of treatment failure is the presence of resistant pathogens. It is now widely found that 30-35% of Haemophilus influenzae and 95-100% of Moraxella catarrhalis produce Image-lactamase, and 35-50% of Streptococcus pneumoniae have intermediate and high-level penicillin resistance. Other factors associated with failure include age, comorbidity, and reduction in FEV1. Based on these factors, a risk stratification for AECOPD has been developed (Table 5).

Table 5. Risk stratification-acute infectious exacerbations of COPD
Table5

This allows classification of patients into four groups, with recommendations for treatment aimed at each specific group. Thus, patients with acute bronchitis with no underlying lung disease should not be given antibiotics, although an exception could be made for those with fever and purulent sputum persisting for 5-7 days from onset. Patients assessed as belonging to group 2 can be treated with -lactams, and fluoroquinolones can also be considered for these patients. Treatment choices for group 3 are diverse, although there is an increasing trend to use fluoroquinolones over the other agents. Group 4 patients with bronchiectasis should receive pathogen-directed treatment, which would encompass a fluoroquinolone plus an additional anti-pseudomonal agent if required.
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Optimal Treatment of AECB High-Risk Patients

Patients at high risk of developing AECB need specific therapeutic strategies aimed at improving their outcome, and these were discussed by Professor S. Ragnar Norrby, Department of Infectious Diseases and Medical Microbiology, University of Lund, Lund, Sweden. He defined those at increased risk as having underlying respiratory illnesses, dyspnoea, fever, or prior admission to hospital, being from a chronic care facility, or having received prior antibiotics. In the past, these patients have been managed with penicillins, cephalosporins, and macrolides, but this situation is rapidly changing with the increasing emergence of resistance worldwide. Resistance to tetracyclines is also widespread. Fluoroquinolones have risen in prominence as they are recognised as having good activity against all of the most common pathogens, and agents such as levofloxacin also cover atypicals and resistant species. Levofloxacin shows no cross resistance with other classes of antibiotics, can be administered parenterally, and has exceptional (almost 100%) oral bioavailability, making sequential therapy easy to administer. In addition due to having a long half-life and advantageous pharmacokinetic features, levofloxacin has a very convenient once-daily dosing schedule.A recent study has confirmed that once-daily levofloxacin 500mg was very effective and was better at bacterial eradication than was standard cephalosporin treatment (Table 6). Clinical trials have proved levofloxacin to be effective in AECB and it is well tolerated. In addition, levofloxacin is safer than other anti-pneumococcal agents, with many of the alternative agents having been withdrawn due to unacceptable toxicity

Table 6. Bacterial eradication rates following once-daily levofloxacin treatment versus cephalosporins
Table6

Taken together, these presentations provided an excellent look at how best to manage patients who present with CAP or AECB. These are common conditions requiring well thought out strategies that can be of practical benefit to the physician. The patients are divided into specific subgroups requiring different approaches for each. These include those at high risk of developing severe disease, as well as those who have failed initial therapy. The approaches are evidence based and supported by the most recent IDSA guidelines for management of these infections. The recurring theme throughout the presentations is the need for a correct diagnosis, followed by risk assessment, which allows optimal management to be instigated. In many of the patients with LRTIs, it is becoming apparent that fluoroquinolones are playing an increasingly pivotal role in treatment.
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