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Highlights from the 10th European Congress of Clinical Microbiology and Infectious Diseases
Stockholm, Sweden, May 28-31, 2000

CONTENTS

Introduction

Latest IDSA Guidelines Confirm Increasing Respiratory Role for Fluoroquinolones

Levofloxacin: An Exceptionally Safe Fluoroquinolone

Resistance Data Update

Clinical Results Confirm Levofloxacin Efficacy in A Range of Infections

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Introduction

The 10th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), held in Stockholm, Sweden from May 28-31, provided an in-depth look at many of the most controversial and perplexing issues facing those working in the field of infectious disease. Previously held every two years, this meeting has now become an annual event due to its increasing prominence among clinicians and researchers alike. ECCMID is one of the few meetings that encompasses both clinical microbiology and infectious diseases, making it possible to gain unique insights into many emerging areas including the interaction between major diseases and micro-organisms. The latest data on resistance were presented, highlighting the increasing incidence, particularly of penicillin-resistant Streptococcus pneumoniae (PRSP), around the world. In this milieu, fluoroquinolones are of particular interest, as the newer 'respiratory' agents continue to have activity against many pathogens resistant to other antimicrobials. Levofloxacin is emerging as one of the leading fluoroquinolones, with excellent activity, wide antibacterial spectrum, and exceptional safety features distinguishing it from many other fluoroquinolones currently available. This report summarizes the most important sessions of the 10th ECCMID devoted to fluoroquinolones, and levofloxacin in particular.

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Latest IDSA Guidelines Confirm Increasing Respiratory Role for Fluoroquinolones

Fluoroquinolone use in respiratory tract infections (RTI), especially community-acquired pneumonia (CAP), was the focus of one symposium. It was emphasized that the indications for using fluoroquinolones have progressively increased. The latest Infectious Disease Society of America (IDSA) Guidelines for CAP reported by Dr. Thomas Marrie, Department of Medicine, University of Alberta, Edmonton, Canada, show that fluoroquinolones are now indicated for the following: outpatient treatment of CAP in immunocompetent patients, those with a suspected penicillin-resistant Streptococcus pneumoniae (PRSP), hospitalized patients (including ICU) in combination with a Image-lactam, and in patients with a penicillin allergy used in combination with clindamycin. Fluoroquinolones are also recommended in combination with metronidazole or clindamycin in suspected aspiration pneumonia. This increase in approved usage is due to the recognition that newer fluoroquinolones, such as levofloxacin, possess not only excellent activity against a wider spectrum of pathogens than their predecessors, but they also cover many resistant organisms. Confirming this trend were clinical trial results, which continue to add weight to the mounting evidence supporting the use of levofloxacin in RTI. Levofloxacin achieved a 100% clinical success rate against penicillin-intermediate resistant S. pneumoniae (PISP) and PRSP isolates. When treating macrolide-resistant S. pneumoniae (MRSP) isolates alone, the clinical success rate was 92% (Table 1). Microbiological eradication rates were similarly exceptional. With S. pneumoniae susceptibility to levofloxacin shown to be independent of penicillin resistance, levofloxacin was described by Dr. Marrie as a good choice for empiric treatment of CAP.

Table 1. Clinical response for CAP with PRSP and/or MRSP

Table1

In addition to clinical efficacy, the impact of levofloxacin and other fluoroquinolones in the development of resistance against S. pneumoniae was discussed by Dr. Henri Drugeon, Laboratoire de Bacteriologie, Hôpital Laennec, Nantes, France. Older agents such as ciprofloxacin are more likely to lead to resistance than levofloxacin. This has been confirmed by animal model data where the first mutant HB 964 was selected from parent strain HB 153 by sparfloxacin (Table 2). The second and third stages were selected by ciprofloxacin but not by levofloxacin. Thus, levofloxacin possesses important advantages over the other fluoroquinolones in terms of being less likely to select for resistance. In this era of growing concern over resistance, this is an important advantage that levofloxacin holds over its competitors.

Table 2. Theoretical development of resistance

Table2

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Levofloxacin: An Exceptionally Safe Fluoroquinolone

One of the other main areas where fluoroquinolones can be distinguished from each other is their safety records. Dr. André Bryskier, Aventis Pharma, Romainville, France, looked at structure-adverse event relationships among these agents. Phototoxicity is a well recognized side effect associated with fluoroquinolones, and it appears to be related to the 8-fluorine atom. Sparfloxacin, lomefloxacin, and fleroxacin are all associated with significant phototoxicity. In contrast, levofloxacin, ofloxacin and ciprofloxacin are less likely to cause phototoxicity. Cardiotoxicity has also been associated with specific fluoroquinolones, in particular sparfloxacin and grepafloxacin. This effect is related to an amino, methyl or other substituents at the fifth position of the quinolone ring, and causes alterations in the HERG potassium transfer channels resulting in corrected QT interval (QTc) prolongation. A strong association between sparfloxacin and cardiac events has been confirmed in both animal and human studies. In contrast, levofloxacin has negligible, if any, cardiac adverse effects. Another major area of concern is the association between fluoroquinolones and central nervous system (CNS) effects. Research has indicated that this is related to binding to the GABA receptor, and those fluoroquinolones having no or low CNS side effects, such as levofloxacin, demonstrate a very low affinity for the GABA receptor (Table 3). Dr. Bryskier concluded that levofloxacin is among the safest of the fluoroquinolones, with its excellent safety and tolerability profile proven in many clinical situations.

Table 3. Affinity for individual fluoroquinolones for GABA receptors with and without NSAIDs

Table3
IC50 = concentration resulting in 50% inhibition.

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Resistance Data Update

An update on resistance patterns was provided by Dr. David Felmingham, GR Micro Ltd., London, UK, who presented Alexander Project and European Susceptibility Survey data. There is considerable global variation among incidence rates of PRSP. Both Spain and France have high-level resistance, and while Ireland has a high-level resistance rate of 23%, there is a sharp drop in Britain where only 6% exhibit high-level resistance. Preliminary Alexander Project data from 1999 illustrated that the rate of S. pneumoniae resistant to penicillin varied from 4.7% in Germany to 47.3% in Spain, with an overall incidence of 19.5%. S. pneumoniae resistance to cephalosporins and trimethoprim-sulfamethoxazole (TMP-SMX) was at a rate of 11.4-12.9% and 30%, respectively (Table 4). Of concern from this update was the fact that penicillin and macrolide resistance is increasing yearly within Europe.

Table 4. Comparative in vitro activity of 20 antimicrobials against 822 community-acquired respiratory tract bacterial pathogens from 7 European countries participating in the 1999 Alexander Project

Table4
a using NCCLS breakpoints for S. pneumoniae (NCCLS, 2000), TMP-SMX = trimethoprim-sulfamethoxazole, NA = not applicable, *No NCCLS breakpoint, follows penicillin susceptibility in S. pneumoniae

Levofloxacin was confirmed to be very active against not only PRSP and H. influenzae, but also M. catarrhalis. While there is limited data on resistance among the atypicals, levofloxacin has been shown to be very active against Legionella spp. (MIC90 0.015 mg/L). In addition, it is more active than ciprofloxacin against Mycoplasma pneumoniae (MIC90 1 mg/L), and is effective against Chlamydia pneumoniae (MIC90 1 mg/L). Thus, levofloxacin possesses excellent coverage over a wide range of important respiratory pathogens.

Concern over multidrug resistance among S. pneumoniae was also raised during sessions of the ECCMID meeting. One presentation by Dr. Clyde Thornsberry et al, MRL Pharmaceutical Services, Brentwood Tennessee, USA, assessed the susceptibility of 2,459 European S. pneumoniae isolates to penicillin, ceftriaxone, azithromycin, TMP-SMX and levofloxacin. Multidrug resistance was defined as resistance to three or more of the study drugs. The most common MDR phenotype (64.3%) covered penicillin, azithromycin and TMP-SMX. The second most common included these three plus ceftriaxone (20.6%). It was noted that resistance to penicillin increased in parallel to increases in MDR rates. Levofloxacin resistance was only very rarely associated with an MDR phenotype, therefore leading Dr. Thornsberry to conclude that levofloxacin provides a valuable alternative for treating infectious diseases because it is unlikely to select for MDR phenotypes.

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Clinical Results Confirm Levofloxacin Efficacy in A Range of Infections

Dr. Eva Coma, Internal Medicine Service, Hospital Sant Pau, Barcelona, Spain reported results comparing levofloxacin 500 mg daily versus ceftriaxone 2 g daily or cefuroxime 1 g daily, with or without a macrolide. A total of 95 patients were evaluable, 48 in the levofloxacin group and 47 in the comparator arm. Both groups had similar baseline characteristics and a similar distribution of causative pathogens. The levofloxacin-treated group had a shorter duration of fever (1.8 versus 2.2 days), a slightly reduced time in hospital (5.1 versus 5.7 days), and a lower readmission rate (1.4 versus 1.9%). Safety investigation revealed that no severe adverse events were reported, with only 4 patients found to have diarrhea in the levofloxacin group. Thus, levofloxacin as monotherapy was as effective as, if not better than, ceftriaxone or cefuroxime plus or minus a macrolide for treating CAP.

Another area where levofloxacin was shown to be effective was in the field of gastroenterology. Dr. Sonja Bötcher, Institute of Hygiene, University of Heidelberg, Germany, assessed the serum and bile concentrations of levofloxacin after two oral doses of 500 mg levofloxacin in patients with biliary obstruction. Twenty-one patients were entered. The mean serum concentrations went from 0 µg/ml to 5.34 µg/ml at 3 hr, 5.07 at 5 hr, 4.23 at 24 hr, 6.04 at 27 hr, and 5.51 at 29 hr. The respective bile concentration figures were: 0 at 0 hr, 10.03 at 3 hr, 7.18 at 5 hr, 4.09 at 24 hr, 8.82 at 27 hr, and 6.56 at 29 hr, reflecting a good correlation between serum and bile concentrations. The drug concentrations of levofloxacin exceeded the MIC90 against many common biliary pathogens over an extended period of time, making it useful for prophylaxis following invasive gastrointestinal procedures which are often associated with complications.

Orthopaedic infections can also be treated by levofloxacin. Twenty-one patients with pressure ulcers were evaluated by Dr. Heike von Baum, Institute of Hygiene, University of Heidelberg, Germany, following 500 mg levofloxacin IV perioperatively. The mean serum concentration was 8.70 ± 2.38 µg/ml. Tissue concentrations were highest in the skin samples (19.9 + 9.9 µg/ml), then wound tissue (17.3 ± 6.5 µg/ml), granulation tissue (13.9 ± 2.59 µg/ml) and lowest in fatty tissue (3.8 ± 1.7 µg/ml) and cortical bone (2.9 ± 1 µg/ml) (Figure 1). Thus, levofloxacin attained peripheral target site concentrations that were consistently above the MICs for most of the problematic pathogens causing wound infections, making it a useful agent for perioperative prophylaxis in orthopaedic patients.

Figure1

Figure 1. Concentration of levofloxacin in serum and tissues of 21 orthopaedic patients.

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Last updated September 25, 2000.