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toumei ../image Congress Report

Highlights from the 15th Asia-Pacific Congress on Diseases of the Chest
Manila Philippines, December 4-8, 1999

CONTENTS

Introduction

High AUC/MIC Ratio for Levofloxacin

Results from an Ongoing International Surveillance Study

Fluoroquinolone Resistance Extremely Low

An Algorithm for Managing CAP

Latest IDSA Guidelines for CAP

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Introduction

The 15th Asia-Pacific Congress on Diseases of the Chest (APCDC) was recently held in Manila, where issues affecting the optimal management of respiratory tract infections (RTIs) were discussed. A great deal of emphasis was placed on the burden of community-acquired pneumonia (CAP) which was described as a "continuing threat despite the best efforts of medical practitioners, researchers and laboratory investigators". With the growing resistance to many agents, it has become imperative that treatment guidelines are prepared that help physicians define which drug(s) to use, and the optimal administration schedule. As well as symposia and scientific sessions focusing upon this topic, a large number of poster sessions presented new data of particular relevance to Asian countries. A common theme to emerge from the meeting was the important role of new fluoroquinolones, such as levofloxacin, in counterattacking the threat of growing resistance. The following paper reports on the highlights of the meeting, focusing on the role of levofloxacin in treating lower respiratory tract infections (LRTIs).

A symposium focusing on the need for evidence-based treatment of LRTIs was held with three world-renowned speakers under the chair of Prof. Maria B. Siasoco, Philippine General Hospital, University of the Philippines, Metro Manila, Philippines. Pharmacological analysis, which is important in developing optimal treatment strategies, was outlined by Prof. Charles H. Nightingale, Hartford Hospital, University of Connecticut School of Pharmacy, Hartford, CT, USA. This was followed by the latest international resistance surveillance results from Dr. Clyde Thornsberry, MRL Pharmaceutical Services, Brentwood, TN, USA. A clear-cut update on the Infectious Diseases Society of America (IDSA) Guidelines for treatment of CAP was then presented by Prof. John G. Bartlett, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

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High AUC/MIC Ratio for Levofloxacin

Pharmacological factors which are now recognized as important indicators of efficacy include a ratio for the area under the plasma concentration versus time curve relative to the minimum inhibitory concentration (AUC/MIC) greater than 100 for Gram-negative organisms and greater than 30 for Gram-positive pathogens. With this in mind, it was clearly demonstrated that levofloxacin possesses extremely advantageous pharmacological features, as it achieves an AUC/MIC against Streptococcus pneumoniae above this threshold of 30, 99% of the time. Further validation of the pharmacological benefits provided by levofloxacin were presented by Prof. Nightingale, who reported results from his own study utilizing 933 real patients (rather than volunteers) and using a Monte Carlo mathematical model. Ninety-two percent of patients had an AUC Image 51, and, in fact, 12% had an AUC Image121. Results confirmed that the certainty of levofloxacin treatment achieving an AUC/MIC greater than 30 was 99% among patients at Hartford Hospital (Figure 1).

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Figure 1. Probability distribution curve AUC/MIC for patients on levofloxacin.
The certainty of achieving a AUC/MIC > 30 was shown to be 99%.
Adapted from Grant EM, et al. Application of population pharmacokinetics and surveillance data to predict AUC/MIC ratios: a Monte Carlo analysis. American Society of Health-System Pharmacists Midyear Clinical Meeting 1999.

Cost-effectiveness issues are continuing to be raised, and with this in mind, Prof. Nightingale reported results from a study comparing the cost of treating a hospitalized patients with CAP for four days intravenously (IV) followed by two days oral (PO) therapy. This study compared the costs associated with azithromycin, cefuroxime axetil and erythromycin combination, and levofloxacin. When all costs were considered, taking into account the safety profile of the different agents, potential drug interactions, and the clinical success and failure rates, the study demonstrated that levofloxacin was the most cost-effective antibiotic to use in this situation (Figure 2). In contrast, the initially cheapest option of cefuroxime axetil and erythromycin combination was found to be the most costly when all factors were considered. It is extremely important that direct drug acquisition costs are not the sole tool for deciding which drug is the cheapest to use. All factors such as efficacy, drug interactions, failure rates and adverse drug reaction (ADR) rates need to be considered as well.

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Figure 2. Antibiotic costs for hospitalized community-acquired pneumonia (4 days IV, 2 days PO).
IV = intravenously, PO = orally.
Adapted from Richerson MA, et al. Pharmacoeconomic evaluation of alternative antibiotic regimens in hospitalized patients with community-acquired pneumonia. Infect Dis Clin Pract 1998; 7: 227-33.

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Results from an Ongoing International Surveillance Study

An international surveillance study was performed to assess the resistance patterns among S. pneumoniae, Haemophilus influenzae and Moraxella catarrhalis, with results reported by Dr. Thornsberry, showing marked variability worldwide. A total of 11,502 isolates were tested from nine countries, using microdilution susceptibility tests as recommended by the National Committee for Clinical Laboratory Standards (NCCLS) Guidelines. Of these, 90% of M. catarrhalis isolates produced Image-lactamase, making it necessary for physicians to consider that, from a clinical perspective, all strains of M. catarrhalis are resistant to ampicillin and amoxicillin.

In contrast, Image-lactamase production by H. influenzae ranged from 5.7% in Germany to 34.5% in the US. All isolates of H. influenzae and M. catarrhalis were susceptible to levofloxacin. Ampicillin resistance among H. influenzae ranged from 5.8% in China to 34.8% in the US. Trimethoprim-sulfamathoxazole (TMP-SMX) resistance ranged from 17.2% in France to 52.9% in Brazil (mean 29.7%).

Enormous differences between countries in the incidence of penicillin resistance were demonstrated. In regard to S. pneumoniae, the mean global incidence of penicillin resistance was 33%, ranging from 7.8% in Germany to 66.5% in France (Table 1). It was emphasized that penicillin resistance in S. pneumoniae was associated with resistance to other Image-lactams, macrolides and sulphonamides, but not to levofloxacin or vancomycin.

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Fluoroquinolone Resistance Extremely Low

When assessing fluoroquinolone resistance, the study focused on levofloxacin, an agent which has been widely used in Japan since 1993 with only minimal resistance developing in S. pneumoniae. One reason for this includes the need for two mutations to confer high- level resistance.

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An Algorithm for Managing CAP

The latest IDSA Guidelines for the management of CAP were presented by Prof. Bartlett. He drew on his wealth of clinical experience to describe a clear management strategy for dealing with a patient who presents with what appears to be an LRTIs. The first step is to make a diagnosis and, in this regard, the importance of the chest X-ray (CXR) is paramount. This not only aids the diagnosis of CAP, but also differentiates this disease from acute bronchitis, a predominantly viral disorder which is associated with a vast amount of over-treatment. The decision for hospitalization should be based on social factors and evaluation of severity of illness. Identification of an etiologic agent for inpatients should include two pretreatment blood cultures, one pretreatment sputum specimen, and seriously ill patients require testing for Legionella spp. Therapy needs to be initiated as soon as possible. An analysis of 14,069 patients demonstrated that survival is influenced by the time interval from patient presentation for health care until they receive their first dose of antibiotic (Figure 3). If this is delayed for more than 8 hours, there is a statistically significant increase in mortality.

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Figure 3. Effect of delayed antibiotic treatment on mortality (n = 14,069 patients > 65 yrs).
CI = Confidence interval
Adapted from Meehan TP, et al. Quality of care, process, and outcomes in elderly patients with pneumonia. JAMA 1997; 278: 2080-4.

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Latest IDSA Guidelines for CAP

Therapy for known etiological agent

  • When treating an infection caused by S. pneumoniae with a penicillin MIC < 2 µg/ml the oral Image-lactams of choice are amoxicillin, cefuroxime axetil, cefprozil and cefpodoxime. Parenteral Image-lactams should include penicillin (or ampicillin, or piperacillin, but not ticarcillin), cefuroxime axetil, although this is marginal, and cefotaxime, ceftriaxone and cefepime. Other agents which could be used include imipenem, fluoroquinolones, and the macrolides, doxycycline and clindamycin although their activity can be variable.
  • When treating penicillin-resistant pneumococcus (MIC > 2 µg/ml) the best choices are fluoroquinolones or possibly vancomycin. However, vancomycin is recommended with caution given the fact that the experience in using this agent in RTIs is limited.

Empiric management of CAP

  • For the empiric treatment of patients who present with suspected pneumonia and who do not require hospitalization, the following agents, in no order of preference, are recommended (Table 2): Doxycycline, or macrolides, or a fluoroquinolone with enhanced activity against the pneumococcus (levofloxacin, moxifloxacin and gatifloxacin).
  • For empiric management of inpatients, a Image-lactam plus a macrolide or a fluoroquinolone alone is recommended.
  • If the patient is critically ill and requires hospitalization in the ICU, the recommendation is for a Image-lactam plus a macrolide or a Image-lactam plus a fluoroquinolone. Very recent work is now available which does point toward a recognition that fluoroquinolones will also be useful as single agents in ICU patients.

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Prediction model for identification of patient risk for persons with community-acquired pneumonia.
This model may be used to help guide the initial decision on site of care; however, its use may not be appropriate for all patients with this illness and therefore should be applied in conjunction with physician judgement.
Adapted from Fine MJ, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med 1997; 336: 243-50.

Prof. Bartlett commented that the latest IDSA Guidelines recommend that fluoroquinolones be used for both outpatients and hospitalized patients. The justification for this recommendation is based upon a number of important benefits provided by fluoroquinolones, as they have been demonstrated to have good activity against the major pulmonary pathogens including pneumococcus, H. influenzae and atypical strains. There are data available from clinical trials to support this choice. In addition, the drugs have a low toxicity profile and can be administered in a very convenient schedule, utilizing both oral and parenteral formulations in a once-daily regimen.

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