New Insights in the Treatment of Severe Infections in the Multiple-Drug Resistant Situation: Satellite Symposium to the 11th International Congress on ... March 2004: Proceedings (Chemotherapy)

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Author: T. M. | Jr. File

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New Insights in the Treatment of Severe Infections in the Multiple-Drug Resistant Situation Proceedings of a Satellite Symposium to the 11th International Congress on Infectious Diseases Cancun, Mexico, March 5, 2004

Guest Editor

Thomas M. File, Jr., Akron, Ohio

14 figures and 9 tables, 2004

Basel • Freiburg • Paris • London • New York • Bangalore • Bangkok • Singapore • Tokyo • Sydney

The symposium and publication were made possible by an educational grant from Daiichi Pharmaceutical Co., Ltd. Editorial development by BIOMEDIS International Ltd.

S. Karger Medical and Scientific Publishers Basel • Freiburg • Paris • London New York • Bangalore • Bangkok Singapore • Tokyo • Sydney

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Drug Dosage The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.

All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center (see ‘General Information’). © Copyright 2004 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel ISBN 3–8055–7822–9

Vol. 50, Suppl. 1, 2004

Contents

1 Introduction File, T.M., Jr. (Akron, Ohio/Rootstown, Ohio) 3 Comparative Antimicrobial Susceptibility of Respiratory Tract

Pathogens Felmingham, D. (London) 11 Experience with Levofloxacin in a Critical Pathway for the Treatment

of Community-Acquired Pneumonia Marrie, T.J. (Edmonton) 16 Clinical Applications of Levofloxacin for Severe Infections Graninger, W.; Zeitlinger, M. (Vienna) 22 New Insights in the Treatment by Levofloxacin File, T.M., Jr. (Akron, Ohio/Rootstown, Ohio)

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Chemotherapy 2004;50(suppl 1):1–2 DOI: 10.1159/000079815

Introduction Thomas M. File, Jr., Symposium Chair Department of Internal Medicine, Summa Health System, Akron, Ohio; Northeastern Ohio Universities College of Medicine, Rootstown, Ohio, USA

In recent years there has been huge interest in infectious diseases, fuelled no doubt by the recent emergence of severe acute respiratory syndrome (SARS) and avian flu viruses. They have provided a timely reminder that pathogens around the world are continually evolving, and that we, as infectious disease specialists, need to keep up to date with the latest trends and developments occurring in our respective specialties. Not only are changes to viruses a problem, but we are also well aware of alterations in pathogenic bacteria. It is with this in mind that ongoing surveillance programs were initiated and some of these now have data going back for more than a decade. These programs are able to show trends in resistance and susceptibility patterns, both within individual countries and around the world. This knowledge is of great importance to increase our understanding of the evolution of resistance, which is then needed to develop protocols to counteract this insidious problem. One of the major concerns in infectious disease is the development of multiple-drug resistant (MDR) pathogens, organisms that can withstand many of the previously recommended antimicrobials. These pathogens are ones that we do not want to spread any further. The scientific content of this publication is based on the need to clearly define the problem of MDR infections, and to develop new, optimal strategies, both to treat the infections and reduce the emergence of further resistance. With this in mind we prepared articles with a global overview, beginning with a recognized world expert on resistance trends, Dr. David Felmingham, Chief Executive of

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G.R. Micro, Ltd., London, UK. Dr. Felmingham explains about the comparative antimicrobial susceptibility of respiratory tract pathogens and presents the latest data from ongoing surveillance studies performed internationally. The use of empirical treatment for most respiratory infections underscores the need for all physicians to know local sensitivity rates in order to effectively treat their patients. An overview of current resistance rates demonstrates that penicillin-resistant Streptococcus pneumoniae (PRSP) remains high (35–70%) around the world. High rates of PRSP are reported in the USA, Mexico, France, Spain, the Slovak Republic, Ireland, South Africa, Israel, Saudi Arabia, Singapore, South Korea, Hong Kong and Japan. Data also clearly shows that where there is penicillin resistance, macrolide resistance is also frequently found. Rates of macrolide-resistant S. pneumoniae (MRSP) are reported to be 70–80% in East Asia, severely limiting the usefulness of these agents in those areas. Other antimicrobials, including trimethoprim-sulphamethoxazole (TMP-SMX) and tetracycline are also often linked to penicillin and macrolide resistance. In sharp contrast, global resistance to the respiratory fluoroquinolones (e.g. levofloxacin, gatifloxacin, moxifloxacin) remains rare, with only isolated incidences of high-level resistance. One such well-known hot spot is Hong Kong where a specific clonal strain of S. pneumoniae is responsible. Other respiratory pathogens noted for increasing resistance to commonly used antimicrobials include Haemophilus influenzae and Moraxella catarrhalis, which both

Prof. Thomas M. File, Jr., MD, MS Department of Internal Medicine, Summa Health System 75 Arch Street, Suite 105, Akron, OH 44304 (USA) Tel. +1 330 375 3894, Fax +1 330 375 3161 E-Mail [email protected]

have widespread ß-lactamase production. Many H. influenzae isolates are also resistant to TMP-SMX. The development of resistant pathogens is severely affecting the empiric management of many infections, making the use of fluoroquinolones, such as levofloxacin, even more attractive as resistance is rare in these pathogens. This is followed by a report on the experience using levofloxacin in a critical pathway for the treatment of community-acquired pneumonia (CAP). Dr. Thomas J. Marrie, Professor and Chair, Department of Medicine, University of Alberta, Edmonton, Canada, is an expert in developing protocols that can guide the practitioner in treating patients with respiratory tract disease, offering clear strategies for admission, treatment and discharge. These protocols have been shown to be cost-effective and of great clinical benefit. He has now turned his attention to what occurs when a suspected pneumonia patient presents to the emergency department. Using seven centers in Edmonton with more than 7,730 patients, Dr. Marrie recently completed a detailed study that will be of great benefit for all who wish to optimize patient care while also making the best use of limited health care resources. His investigation into the use of levofloxacin in a clinical setting using a critical pathway is therefore of great interest. The pathway allowed the practicing physicians to see how well levofloxacin worked in a ‘real’ situation. This trial found that the overall mortality rate for CAP patients was 8%; increasing pneumonia severity risk score was associated with increased early (less than five days) and late mortality (five days or more). The use of the clinical pathway was associated with a reduction in the early mortality rate. Patients treated with levofloxacin alone, or a combination of cefuroxime axetil plus azithromycin, had a lower late mortality rate. The pathway provides a clear guideline for improving the empiric management of patients presenting to emergency departments with suspected CAP. The significant issue of serious infections is addressed by the remaining two articles, both of which describe the utility of a 750-mg dose of levofloxacin in the management of patients with respiratory tract infections (RTIs). This new high-dose therapy has been proposed after consideration of the pharmacodynamic (PD) features of levofloxacin. As a concentration-dependent agent, the bactericidal activity of levofloxacin is most closely related to the maximum concentration to minimal inhibitory concentration ratio (Cmax/MIC) and area under the curve to minimal inhibitory concentration ratio (AUC/MIC), both of which increase as the dose of the drug increases. This is

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Chemotherapy 2004;50(suppl 1):1–2

associated with greater tissue penetration and a likely reduction in resistance pressure. Professor Wolfgang Graninger, Head, Division of Infectious Diseases and Chemotherapy Internal Medicine, University of Vienna, Austria, discusses the issue of severe infections in critically ill patients. Although there are a range of antimicrobial therapies available for common infections, the difficulty arises when deciding how to treat critically ill patients, where rapid and effective management is paramount. In this situation, fluoroquinolones, particularly levofloxacin, are recommended because of their excellent features, including a large antibacterial spectrum of activity, extremely high bioavailability and good safety record. In order to treat the most severe infections it is also becoming accepted to use a higher dose of 750 mg levofloxacin. This is based on its concentrationdependent PD features, which result in a greater probability of a good clinical outcome as the agent increases in dose. Unlike many other fluoroquinolones, levofloxacin can be safely increased in dose, thereby providing it with advantages over many other agents. Continuing this theme of high-dose levofloxacin in the treatment of severely ill patients, I present a report on new insights in treatment by levofloxacin. The higher dose schedule has previously been approved for complicated skin and skin structure infections (CSSSIs) and nosocomial pneumonia. The latest data now available details results using this high-dose strategy and demonstrates its efficacy and safety in managing seriously ill patients, including a very recent study comparing a short-course, 5-day therapy of high-dose levofloxacin to the conventional 10-day regimen. This study further supports the usefulness of the high-dose strategy. This new administration schedule offers many potential advantages to the physician and patient alike by reducing the time and total amount of drug required for a course of therapy. In addition, the study found that patients treated in the high-dose levofloxacin group had quicker resolution of symptoms and quicker change from IV to PO therapy. This can result in a significant cost-saving benefit. The aim of this publication is to provide readers with an understanding of the escalating problem of MDR infections and the optimal management of these serious infections. I hope that it offers a greater insight into these issues.

File


Comparative Antimicrobial Susceptibility of Respiratory Tract Pathogens David Felmingham G.R. Micro Ltd., London, UK

Key Words Resistance W Surveillance W Levofloxacin W Macrolides W Respiratory tract infections

Abstract Bacterial respiratory tract infections (RTIs), whether primary or subsequent to viral infection, are a frequent cause of morbidity and mortality worldwide. Treatment of these infections is most often empirical. Therefore, an antimicrobial’s antibacterial spectrum must include the most likely pathogens: Streptococcus pneumoniae, the most frequent cause of community-acquired pneumonia (CAP), Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus, as well as atypicals such as Mycoplasma pneumoniae, Legionella pneumophila and Chlamydophila (Chlamydia) pneumoniae. In addition, knowledge of antimicrobial resistance among these key pathogens is imperative for physicians to choose the most appropriate therapeutic agent. The latest data from global surveillance studies indicates that high-level resistance to penicillin (MIC 6 2 mg/l) among isolates of S. pneumoniae varies widely by geographic location. Rates exceed 20% in the USA, Mexico, Japan, Saudi Arabia, Israel, Spain, France, Greece, Hungary, and the Slovak Republic. In South Africa, Hong Kong, Taiwan, and South Korea rates exceed 50%. Penicillin non-suscepti-

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bility – including isolates exhibiting high-level resistance and intermediate susceptibility (MIC 0.12–1 mg/l) – is frequently found in association with macrolide resistance, which is found at a prevalence of 70–80% in some Asian countries. Trimethoprim-sulfamethoxazole (TMP-SMX) and tetracycline resistance, either individually or combined with macrolide resistance as multiple resistance, is also associated with reduced susceptibility to penicillin. Another concern about antimicrobial resistance in respiratory tract pathogens is ß-lactamase production among isolates of H. influenzae and M. catarrhalis. However, respiratory fluoroquinolones, of which levofloxacin has been available for the longest time, currently remain active against the great majority of common bacterial respiratory pathogens, including atypicals. Copyright © 2004 S. Karger AG, Basel

Introduction

The Alexander Project, begun in 1992, and the Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin (PROTEKT) studies, begun in 1999, have produced surveillance data for the past 12 years. This data was used to review the prevalence of resistance and the frequency of occurrence of known and novel resistance mechanisms (genotypes) among com-

Dr. David Felmingham, Chief Executive GR Micro Ltd., 7–9 William Road London NW1 3ER (UK) Tel. +44 20 7388 7320, Fax +44 20 7388 7324 E-Mail [email protected]

Fig. 1. Intermediate/high-level penicillin and amoxicillin non-susceptibility (%) among S. pneumoniae isolates.

monly isolated respiratory tract pathogens. The data summarizes global trends and their potential impact on empirical choice of antimicrobials for the treatment of respiratory tract infections [1–11].

High Global Rates of Penicillin Non-Susceptible S. pneumoniae

Streptococcus pneumoniae is the most important bacterial respiratory tract infection (RTI) pathogen in terms of morbidity and mortality. It is the major cause of community-acquired pneumonia (CAP) and an important pathogen in sinusitis, otitis media and acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Rational empirical choice of antimicrobials for the treatment of RTIs caused by S. pneumoniae must now take account of globally established non-susceptibility to penicillin, which was once first-line therapy for all patients who were not immunologically hypersensitive to this compound. Isolates inhibited by 0.06 mg/l penicillin or less are considered fully susceptible to this ß-lactam. Those re-

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quiring an MIC of 0.12–1 mg/l are described as exhibiting intermediate resistance (low-level resistance) and those requiring an MIC 6 2 mg/l are considered resistant (highlevel resistance). Originally, these definitions were used to classify susceptibility, or lack of it, to aminomethyl penicillins such as amoxicillin (with or without the ß-lactamase inhibitor clavulanic acid). However, more recent analysis of the pharmacokinetic and pharmacodynamic properties of amoxicillin have resulted in the establishment of higher breakpoints by the National Committee for Clinical Laboratory Standards (NCCLS) of the USA for isolates of S. pneumoniae causing infections other than meningitis (susceptible, MIC ^2 mg/l; intermediate, MIC = 4 mg/l; resistant, MIC 68 mg/l) [12]. Current surveillance data reveal high rates of non-susceptibility (low-level and high-level resistance) to penicillin among isolates of S. pneumoniae, which vary considerably by geographic location (fig. 1). Rates of resistance to penicillin and other antimicrobials vary considerably not only between countries which are geographically well separated, but also between those which are adjacent, almost certainly reflecting differences in prescribing practice. In addition, as exemplified by a large study in the USA

Felmingham

Macrolide, Tetracycline and TMP-SMX Resistance More Prevalent than Penicillin Resistance in the Far East

(PROTEKT), rates may also vary substantially on a national basis [13, 14]. A comparison of penicillin resistance rates observed in the USA and Canada emphasizes these differences. In the USA, approximately 30% of isolates of S. pneumoniae examined recently were characterised by high-level resistance to penicillin (MIC 62 mg/l) and half of these isolates also exhibited reduced susceptibility to amoxicillin (intermediate, MIC = 4 mg/l; resistant, MIC 68 mg/l). In contrast, in Canada, high-level penicillin resistance was 9.7% of S. pneumoniae isolates and amoxicillin non-susceptibility was only 1% of this bacterial population. This marked difference between two developed North American countries highlights the need for physicians and public health specialists to be aware of local resistance rates. It may also provide valuable insights into the factors influencing the evolution of resistance by comparison of medical practices. Additionally, modern travel habits present the physician with a further complicating factor, the likely geographical location of acquisition of an infection, which must also influence empirical therapeutic choice. There are a number of hot spots of penicillin-resistant S. pneumoniae (PRSP) around the world. South Africa, where more than 50% of isolates examined recently showed high-level resistance to penicillin and 24% also exhibited reduced susceptibility to amoxicillin, is one example. PRSP rates are even higher in parts of the Far East, exceeding 50% in Taiwan (58.4%), Hong Kong (60.8%), and South Korea (61%), combined with varying rates of reduced susceptibility to amoxicillin (9.5, 12.2, and 30.1%, respectively). PRSP rates vary widely in Europe with a general trend for lower rates in northern European countries compared to those bordering the Mediterranean and in Eastern Europe. High-level penicillin resistance is found in approximately one half of isolates of S. pneumoniae examined in France, while it is comparatively low in Germany and rarely seen in the Netherlands. There is a low prevalence of reduced susceptibility to amoxicillin in most European countries; rates exceed 10% in France (10.2%) and Spain (17.2%) reflecting the higher MIC of penicillin for isolates of S. pneumoniae in these countries. Of note is the difference in rates of penicillin non-susceptibility found among isolates of pneumococci from the Czech Republic (5.6%) and Slovak Republic (49%), two countries which were, until recently, one. Reasons for this consistently observed difference may include prescribing practices, geographical spread of sampling, and the possibility of clonal hot spots.

Penicillin resistance is not the only cause of concern to infectious disease physicians. Other agents that have been used in the past now have reduced activity against common RTI pathogens. Of particular concern is resistance to macrolides (erythromycin, clarithromycin, azithromycin) which in S. pneumoniae occurs principally as a result of either methylation of the 23SrRNA target site (erm Bmediated) or an efflux mechanism (mef A-mediated). In the USA, 32.5% of pneumococcal isolates are currently macrolide-resistant with the efflux mechanism predominant. Rates of 25.8% in Mexico, 52.7% in South Africa, 77.0% in Hong Kong, 80.4% in Japan, and 90.5% in Taiwan were found, with the methylation mechanism of resistance most frequently observed. Unusually, a comparatively high prevalence of macrolide resistance mediated by a combination of the methylation and efflux mechanisms is found among isolates of S. pneumoniae in South Korea and South Africa [15–17]. Resistance to the macrolide erythromycin in S. pneumoniae, as with penicillin resistance, varies widely in Europe with high rates in France (60.6%), Greece (48.6%), and Italy (35.6%), and rates less than 15% in the Netherlands, Portugal, Austria, the Czech Republic, and Poland (fig. 2). High rates of macrolide resistance are often, but not always, seen in association with penicillin non-susceptibility. Tetracycline, a previously useful agent for the treatment of RTIs is also losing clinical efficacy due to increasing resistance among S. pneumoniae isolates. Almost 95% of pneumococcal isolates from Taiwan are now tetracycline resistant with high rates (greater than 25%) also found in Japan, South Africa, Western Russia, Saudi Arabia, Belgium, Spain, France, Italy, Greece, Hungary, the Slovak Republic, and Poland. TMP-SMX is another agent that has lost ground in its activity against S. pneumoniae. Worldwide rates of resistance suggest TMP-SMX is no longer a rational choice for the empirical treatment of RTIs. Resistance rates exceeding 30% are now common around the world, and more than 50% of isolates in Mexico, Brazil, South Africa, Hong Kong, Taiwan, South Korea, and Spain are resistant (fig. 3).

Antimicrobial Susceptibility of RTPs


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Fig. 2. Prevalence of erythromycin resistance among S. pneumoniae isolates.

Fig. 3. Prevalence of TMP-SMX non-susceptibility among S. pneumoniae isolates.

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Felmingham

Fig. 4. Prevalence of multiple resistance (eryR + tetR +TMP-SMXR) among S. pneumoniae isolates.

Multi-Drug Resistant S. pneumoniae

In contrast to many other antimicrobials commonly prescribed for the treatment of RTIs, global resistance to levofloxacin among S. pneumoniae isolates remains at a

very low level (fig. 5). Overall rates range from 0.0 to 2.1% in all countries examined except Hong Kong, where approximately 10% of isolates exhibited high-level fluoroquinolone resistance as a consequence of the circulation of mutants of the Spain 23F-1 clone. Analysis of the Spain 23F-1 clone circulating in Hong Kong revealed three different mutants separated by the nature of mutations in the QRDR region of genes encoding the GyrA subunit of DNA-gyrase (topoisomerase II) and in the Par C and Par E subunits of topoisomerase IV. Of a total of 18 isolates examined from PROTEKT Year 1 and 2, 14 were characterised by the combination of mutations in Gyr A (a DNA-gyrase subunit) resulting in a change from serine to phenylalanine at position 81, and in Par C (a topoisomerase IV subunit) from serine to phenylalanine at position 79. Three isolates carried mutations resulting in changes from serine to tyrosine at position 81 of GyrA and from aspartate to asparagine at position 435 of Par E (a topoisomerase IV subunit). One isolate carried three mutations: serine to tyrosine at position 81 on Gyr A, serine to phenylalanine at position 79 on Par C, and aspartate to asparagine at position 435 on Par E



Although there is concern about the increasing prevalence of resistance to single agents among pneumococci, the problem of multi-drug resistance (resistance to three or more unrelated compounds with or without associated resistance to penicillin) is an increasing worry. Combined resistance to macrolides, tetracycline and TMP-SMX is now observed in more than 50% of isolates of pneumococci in Hong Kong, Taiwan, and South Korea, and in more than 15% of isolates from South Africa, Spain, France, Greece, Hungary, and the Slovak Republic (fig. 4). Unexpectedly, in East Asia, multi-drug resistance in Japan is relatively uncommon (7.2%).

Levofloxacin Maintains Activity Against S. pneumoniae

7

Fig. 5. Prevalence of levofloxacin non-susceptibility among S. pneumoniae isolates.

Table 1. QRDR mutations in Spain 23F-1 clone

GyrA

ParC

ParE

n

Year 1

Ser81 → Phe Ser81 → Tyr

Ser79 → Phe Ser79 → Phe

– Asp435 → Asn

9 1

Year 2

Ser81 → Phe Ser81 → Tyr

Ser79 → Phe –

– Asp435 → Asn

5 3

(table 1). This analysis demonstrates that within the Spain 23F-1 clone at least three different mutations resulting in fluoroquinolone (levofloxacin) resistance have arisen rather than the establishment of a single clone. Furthermore, multi-locus sequence typing of 35 levofloxacinresistant isolates of S. pneumoniae from PROTEKT GLOBAL Year 1 (1999–2000) and 45 from Year 3 (2001– 2002) found 20 different MLS types in Year 1 and 28 in Year 3. Only 3 MLS types were found in both years: sequence type 81 (Spain 23F-1), type 180 (a common

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clone with no special designation), and type 236 (the multi-resistant Taiwanese 19F clone). These data considered together support the view that, at present, levofloxacin resistance in S. pneumoniae is a result of isolated mutational events rather than clonal spread.

Antimicrobial Resistance Among other Bacterial RTI Pathogens

Although antimicrobial resistance in S. pneumoniae is pre-eminent in the minds of infectious disease physicians and microbiologists, evolving resistance in other bacterial respiratory tract pathogens is also of concern. Streptococcus pyogenes remains universally fully susceptible to penicillin. However, this important pathogen is now demonstrating resistance to alternative therapeutic agents, especially macrolides (erythromycin, clarithromycin, azithromycin) and cyclines (tetracyclines) at varying rates around the world [18]. Macrolide resistance is observed in 15% or more of S. pyogenes isolates in South Africa, Hong Kong, Taiwan, South Korea, Japan, Portugal, Spain, France, Italy,

Felmingham

Fig. 6. Prevalence of ß-lactamase production among H. influenzae isolates.

Greece, Hungary, the Slovak Republic, the Czech Republic, and Poland. Tetracycline resistance is also well established in this species in a number of countries at rates of 15% or more of isolates from Brazil, Taiwan, South Korea, Japan, Italy, the Slovak Republic, the Czech Republic, and Poland. In contrast, studies show that the vast majority of isolates of S. pyogenes from around the world remain fully susceptible to levofloxacin, which may thus be considered as a rational alternative therapeutic choice in appropriate patients. Although less frequently associated with communityacquired bacterial RTIs than other species, Staphylococcus aureus is nevertheless a potential pathogen in this clinical disease environment. Aside from ß-lactamase production, which is evident in the great majority of isolates of S. aureus and should be assumed when considering treatment of an infection which may involve this species, methicillin-resistant S. aureus (MRSA) strains are the greatest cause of concern. Of 2,143 S. aureus isolates causing various communityacquired RTIs examined in PROTEKT GLOBAL Year 3 (2001–2002), 17.2% were methicillin resistant. Overall, 80.5% of the 2,143 isolates were susceptible to levofloxacin

and there was a very strong association between methicillin resistance and non-susceptibility to levofloxacin. The data from PROTEKT GLOBAL Year 3 (2001–2002) indicates that levofloxacin may have a role in the treatment of community-acquired RTIs thought to involve S. aureus when methicillin-resistant strains are unlikely and ß-lactamase stable penicillins are contra-indicated. ß-lactamase production is the principal mechanism of antimicrobial resistance found in Haemophilus influenzae and Moraxella catarrhalis. Rates of enzyme production in H. influenzae vary worldwide with prevalence of 10–20% in Canada, Brazil, Saudi Arabia, Israel, the UK, the Republic of Ireland, Belgium, Portugal, Spain, Switzerland, and Greece, and in excess of 20% in the USA, Mexico, France, Hong Kong, Taiwan, and South Korea (fig. 6). Although there is little evidence of the widespread evolution of acquired resistance to macrolides (erythromycin, clarithromycin, azithromycin) and ketolides (telithromycin), these compounds are characterized by a considerably lower potency against H. influenzae (mode MIC 1–8 mg/l) than against Streptococcus spp. In contrast, levofloxacin (mode MIC 0.015 mg/l) and other fluoroquinolones are exquisitely active against H. influenzae and



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clinical resistance is extremely rare. The situation is very similar with isolates of M. catarrhalis, which must now all be considered as ß-lactamase producers when isolated in the clinical environment, but remain in the great majority of cases susceptible to all other classes of antimicrobials, other than ß-lactamase susceptible penicillins, including levofloxacin and other fluoroquinolones [19]. Finally, although inadequate data on the incidence of disease caused and the prevalence of any acquired antimicrobial resistance is available for large, worldwide populations of atypical RTI pathogens, levofloxacin is very active against isolates of Chlamydophila (Chlamydia) pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila.

Conclusion

Established resistance to most classes of antimicrobials otherwise suitable for the treatment of community-acquired upper and lower RTIs complicates empirical therapeutic choice. Levofloxacin, however, remains potently active against the great majority of isolates of S. pneumoniae, H. influenzae, M. catarrhalis, and S. pyogenes worldwide. In addition, the antibacterial spectrum of levofloxacin includes the atypicals L. pneumophila, M. pneumoniae and C. (Chlamydia) pneumoniae. This in vitro data supports the continuing consideration of levofloxacin as a rational therapeutic option for the treatment of a wide range of RTIs.

References 1 Inoue M, Lee NY, Hong SW, Lee K, Felmingham D: PROTEKT 1999–2000: a multicentre study of the antibiotic susceptibility of respiratory tract pathogens in Hong Kong, Japan and South Korea. Int J Antimicrob Agents 2004;23: 44–51. 2 Doern GV, Brown SD: Antimicrobial susceptibility among community-acquired respiratory tract pathogens in the USA: data from PROTEKT US 2000–01. J Infect 2004;48:56–65. 3 Waites K, Brown S: Antimicrobial resistance among isolates of respiratory tract infection pathogens from the southern United States: data from the PROTEKT US surveillance program 2000/2001. South Med J 2003;96:974– 985. 4 Mendes C, Marin ME, Quinones F, SifuentesOsornio J, Siller CC, Castanheira M, Zoccoli CM, Lopez H, Sucari A, Rossi F, Angulo GB, Segura AJ, Starling C, Mimica I, Felmingham D: Antibacterial resistance of community-acquired respiratory tract pathogens recovered from patients in Latin America: results from the PROTEKT surveillance study (1999– 2000). Braz J Infect Dis 2003;7:44–61. 5 Hoban D, Waites K, Felmingham D: Antimicrobial susceptibility of community-acquired respiratory tract pathogens in North America in 1999–2000: findings of the PROTEKT surveillance study. Diagn Microbiol Infect Dis 2003;45:251–259. 6 Gruneberg RN: Global surveillance through PROTEKT: the first year. J Chemother 2002; 14(suppl 3):9–16. 7 Felmingham D: Evolving resistance patterns in community-acquired respiratory tract pathogens: first results from the PROTEKT global surveillance study. Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin. J Infect 2002;44(suppl A):3–10.

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8 Karlowsky JA, Thornsberry C, Critchley IA, Jones ME, Evangelista AT, Noel GJ, Sahm DF: Susceptibilities to levofloxacin in Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis clinical isolates from children: results from 2000–2001 and 2001– 2002 TRUST studies in the United States. Antimicrob Agents Chemother 2003;47:1790– 1797. 9 Karlowsky JA, Thornsberry C, Jones ME, Evangelista AT, Critchley IA, Sahm DF; TRUST Surveillance Program: Factors associated with relative rates of antimicrobial resistance among Streptococcus pneumoniae in the United States: results from the TRUST Surveillance Program (1998–2002). Clin Infect Dis 2003;36:963–970. 10 Karlowsky JA, Kelly LJ, Thornsberry C, Jones ME, Evangelista AT, Critchley IA, Sahm DF: Susceptibility to fluoroquinolones among commonly isolated Gram-negative bacilli in 2000: TRUST and TSN data for the United States. Tracking Resistance in the United States Today. The Surveillance Network. Int J Antimicrob Agents 2002;19:21–31. 11 Thornsberry C, Sahm DF, Kelly LJ, Critchley IA, Jones ME, Evangelista AT, Karlowsky JA: Regional trends in antimicrobial resistance among clinical isolates of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the United States: results from the TRUST Surveillance Program, 1999– 2000. Clin Infect Dis 2002;34(suppl 1):S4– S16. 12 National Committee for Clinical Laboratory Standards. 2004. Performance standards for antimicrobial susceptibility testing, 14th informational supplement. Approved standard M100-S14. National Committee for Clinical Laboratory Standards, Wayne, Pa.


13 Canton R, Morosini M, Enright MC, Morrissey I: Worldwide incidence, molecular epidemiology and mutations implicated in fluoroquinolone-resistant Streptococcus pneumoniae: data from the global PROTEKT surveillance programme. J Antimicrob Chemother 2003;52: 944–952. 14 Schito AM, Schito GC, Debbia E, Russo G, Linares J, Cercenado E, Bouza E: Antibacterial resistance in Streptococcus pneumoniae and Haemophilus influenzae from Italy and Spain: data from the PROTEKT surveillance study, 1999–2000. J Chemother 2003;15:226–234. 15 Farrell DJ, Morrissey I, Bakker S, Morris L, Buckridge S, Felmingham D: Molecular epidemiology of multiresistant Streptococcus pneumoniae with both erm(B)- and mef(A)-mediated macrolide resistance. J Clin Microbiol 2004;42:764–768. 16 Farrell DJ, Douthwaite S, Morrissey I, Bakker S, Poehlsgaard J, Jakobsen L, Felmingham D: Macrolide resistance by ribosomal mutation in clinical isolates of Streptococcus pneumoniae from the PROTEKT 1999–2000 study. Antimicrob Agents Chemother 2003;47:1777–1783. 17 Farrell DJ, Morrissey I, Bakker S, Felmingham D: Molecular characterization of macrolide resistance mechanisms among Streptococcus pneumoniae and Streptococcus pyogenes isolated from the PROTEKT 1999–2000 study. J Antimicrob Chemother 2002;50(suppl S1):39–47. 18 Canton R, Loza E, Morosini MI, Baquero F: Antimicrobial resistance amongst isolates of Streptococcus pyogenes and Staphylococcus aureus in the PROTEKT antimicrobial surveillance programme during 1999–2000. J Antimicrob Chemother 2002;50(suppl S1):9–24. 19 Hoban D, Felmingham D: The PROTEKT surveillance study: antimicrobial susceptibility of Haemophilus influenzae and Moraxella catarrhalis from community-acquired respiratory tract infections. J Antimicrob Chemother 2002; 50(suppl S1):49–59.

Felmingham


Experience with Levofloxacin in a Critical Pathway for the Treatment of Community-Acquired Pneumonia Thomas J. Marrie Department of Medicine, University of Alberta, Edmonton, Alberta, Canada

Key Words Clinical pathway W Community-acquired pneumonia W Epidemiology W Levofloxacin W Management guidelines

Abstract Community-acquired pneumonia (CAP) is associated with considerable morbidity and mortality in both developed and developing countries. Despite research into the optimal management of this condition, there remains great variation in how patients with CAP are treated. A study was performed to assess the results of CAP treatment using a clinical pathway that incorporated admission guidelines, standard treatment orders with oral levofloxacin or cefuroxime axetil plus azithromycin, and an algorithm for oxygen therapy and discharge. The study involved seven centers enrolling 7,734 patients, 55% of whom were treated as outpatients and the remainder were admitted. Overall mortality was 8%, and increasing severity of illness, as assessed by pneumonia severity risk score, was associated with early mortality (within five days of admission) and late mortality (five or more days following admission). The use of the clinical pathway was associated with a reduction in early mortality. The use of levofloxacin alone or with cefuroxime axetil plus azithromycin was associated with decreased mortality compared with the use of other antibiotics.

Introduction

Pneumonia is a common and serious infection that usually requires empiric therapy. Epidemiological data reveals that each year in the US there are 2–3 million cases of community-acquired pneumonia (CAP), resulting in 10 million primary care physician visits and 600,000 hospitalizations. CAP is the sixth leading cause of death in the US and, despite its prominence, there is considerable variation in all aspects of its treatment [1]. There are more than 100 microbial causes of CAP, making etiological diagnosis difficult to confirm. Empiric treatment is therefore the norm, but recommendations are often based on studies that have strict inclusion guidelines ensuring that only patients with pneumonia are analyzed. However, this is not practical in reality. To assess optimal management of patients clinically diagnosed with pneumonia, a study was recently performed in Edmonton, Alberta, Canada, a city with a population of 1 million (665,000 adults). All patients presenting to six hospitals and one freestanding emergency room were enrolled if they met the criteria of having two or more of a variety of respiratory symptoms and physical findings in the chest and a chest radiograph (CXR) read by the attending physician as pneumonia. Patients were managed according to a clinical pathway, which included admission guidelines, treatment op-

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Thomas J. Marrie, MD, Professor and Chair Department of Medicine, University of Alberta 2F1.30, WMC, 8440–112 Street Edmonton, Alberta, T6G 2B7 (Canada) Tel. +1 780 407 6234, Fax +1 780 407 3132, E-Mail [email protected]

Fig. 1. Numbers and percent of patients in each of the critical pathway stages over a two-year period.

tions, and a discharge algorithm. Standard treatment orders included the choice of two antibiotics: oral levofloxacin or, for those vomiting or hypotensive, intravenous (IV) cefuroxime axetil plus azithromycin. An algorithm was also used to monitor the use of oxygen. All patients admitted to the intensive care unit (ICU) were excluded, along with pregnant or nursing women, immunosuppressed, and those with tuberculosis or cystic fibrosis. In the first year of the study, patients with possible aspiration pneumonia were excluded due to a lack of agreement on therapy. In the second year, all such patients were included.

More Than Half of CAP Patients Managed in an Ambulatory Setting

During the two-year study, 9,558 patients were diagnosed with pneumonia, however 19% were excluded. Exclusions were due to admission to ICU (38%), aspiration pneumonia in the first year (19.3%) and physician’s choice (7.3%), while the remainder were due to granulocytopenia, cystic fibrosis, and others. The pathway included 7,734 patients. Of the patients who presented to the emergency room, 55% were managed on an ambulatory basis, while the remainder were hospitalized (fig. 1).

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Demographic analysis demonstrated that pneumonia patients were generally older and more likely to be men. The rates of admission for men were significantly higher than for women. The gender difference in admission rates increased with increasing age, so that men aged 80 years or older had double the admission rate of women (fig. 2). The mortality rate for pneumonia is also lower in women, suggesting there are obvious biological differences that need to be investigated. Site of treatment also differed according to age; 70% of younger patients were treated as outpatients, while 80% of patients aged over 80 years were admitted to hospital for CAP treatment. However, a developing trend of older patients being treated at home was noted. Once admitted, younger patients had a greater likelihood of requiring management in an ICU: 25–35% of those under 40 years of age required ICU treatment. As patients aged, the percent requiring ICU management decreased; only 5% of those aged 85–90 years were admitted to the ICU. This was a six-fold decrease compared to younger patients. A subanalysis of all data on patients admitted to the ICU is now being analyzed to investigate the difference in ICU admission rates according to age. A recent publication looking at ICU admission of Medicare patients in the US reported an 11% ICU admission rate, which differs from the Canadian experience.

Marrie

Fig. 2. Male and female pneumonia admission rate in year 2 (* statistically significant different at 0.05 level).

Fig. 3. The most used antibiotic when only

one antibiotic was used for inpatient.

In practice, 199 (5%) outpatients had a sputum culture performed and there was a positive identification of a pathogen in 87 (44%). In comparison, sputum cultures were taken in 1,190 (35%) inpatients with identification of a pathogen in 343 (29%). Blood cultures were performed on 793 (20%) outpatients with positive identification in 41 (5.2%). Inpatient results were similar with positive identification in 154 (6.9%) patients from a total of 2,239 blood cultures (66%). Streptococcus pneumoniae was the primary pathogen found in 59% of outpatients and 49% of inpatients with positive blood cultures. It is interesting that 22% of the patients with positive blood

culture results for S. pneumoniae were treated as outpatients. Once enrolled in the study, 58.9% of inpatients received only one antibiotic, 24.4% two antibiotics, 12% three antibiotics, and 4.6% four or more antibiotics. The most commonly prescribed antibiotic was levofloxacin when only one was prescribed. At least 90% of patients initially received levofloxacin (fig. 3). An azithromycin/ cefuroxime axetil combination was used in a small number of patients. When more than one antibiotic was administered, the most common strategy was to use levofloxacin plus metronidazole, given when a Clostridium difficile diarrhea developed; levofloxacin and clindamycin, given to patients with aspiration pneumonia, and a number of other less rational combinations. The effect

Levofloxacin in a Critical Pathway for CAP


More Than 20% of Bacteremic Pneumococcal Pneumonia Treated as Outpatients

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Fig. 4. Time from admission to death.

Fig. 5. Kaplan-Meier cumulative hazard for

all-cause mortality by risk class.

of these combinations becomes more important when evaluating the effect of treatment on mortality.

Identification of Factors Associated with Increased Mortality

The overall mortality rate was 8.1% (246/3,043), which is within the range of what is usually reported even when ICU patients are excluded. The mortality pattern in

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hospital had a bimodal distribution, with 30% of deaths occurring within the first three days of admission, rising to 40% within five days, and 60% dying later due to the affect of comorbid diseases exacerbated by the pneumonia (fig. 4). Multivariate analysis indicated that different factors predicted early versus late mortality. Mortality was plotted according to severity of pneumonia using the scale derived from the Patient Outcomes Research Team (PORT) study with patients stratified into five risk categories according to 20 variables. Those in pneumonia

Marrie

severity index (PSI) risk classes I, II and III are at low risk of mortality, whereas those in classes IV and V are at high risk of mortality (fig. 5).

Levofloxacin Use Associated with Decreased Mortality

The affect of antibiotics on mortality revealed that patients who received levofloxacin alone had a 5.3% mortality rate, similar to those treated with cefuroxime axetil plus azithromycin (5.4%), indicating a good outcome in those patients who did not require second level therapy. However, when patients required treatment with other agents, they had a much greater likelihood of mortality (12.3%). The only factor that was seen to be protective for late mortality was the use of levofloxacin. Further analysis needs to be done to confirm whether this is a true effect or a result of confounding by the study design.

Levofloxacin in a Critical Pathway for CAP

Conclusions

The use of the clinical pathway was found to be beneficial for the treatment of pneumonia. It provided clear guidelines for admission, treatment, and discharge. A number of factors were shown to be associated with early and late mortality, including the severity of illness as assessed by PSI risk score.

Acknowledgements This research was supported by an establishment grant from Alberta Heritage Foundation for Medical Research and by grants from Capital Health, Pfizer Canada, Abbott Canada, and Jannsen Ortho Canada.

Reference

1 Bartlett JG, Dowell SF, Mandell LA, File TM Jr , Musher DM, Fine MJ: Practice guidelines for the management of community-acquired pneumonia in adults. Infectious Diseases Society of America. Clin Infect Dis 2000;31:347– 382.


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Clinical Applications of Levofloxacin for Severe Infections Wolfgang Graninger Markus Zeitlinger Department of Medicine, Division of Infectious Diseases and Chemotherapy, University of Vienna, Vienna, Austria

Key Words Levofloxacin W High dose W Nosocomial pneumonia W Critically ill patients W Safety

effective, it is also well tolerated and provides the physician with an additional therapeutic option to manage critically ill patients. Copyright © 2004 S. Karger AG, Basel

Abstract New fluoroquinolones, as exemplified by levofloxacin, possess broad spectrum activity against many common pathogens, including the majority responsible for respiratory tract infections (RTIs), atypical pathogens and those resistant to other therapeutic regimens. Following administration, levofloxacin attains high intracellular and tissue levels. This, coupled with an exceptional pharmacodynamic profile, allows levofloxacin to be administered once daily. However, in certain circumstances, such as seriously ill patients or those with difficult-totreat pathogens, higher doses may be required. Since the bactericidal effect of levofloxacin is concentrationdependent, it is possible to increase peak concentration by increasing the dose, resulting in even better tissue concentration (and a possible reduction in the development of resistance). High-dose levofloxacin is able to exploit these pharmacokinetic features to provide an effective treatment for severe infections. Data is now available confirming the efficacy of high-dose levofloxacin in a wide range of infections, including nosocomial pneumonia, meningitis and complicated skin and skin structure infections (CSSSIs). Not only is this regimen

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Introduction

Levofloxacin is recognized as a leading clinically effective antimicrobial agent for the treatment of a wide range of infectious diseases, including community-acquired pneumonia (CAP). Although fluoroquinolones possess many extremely useful features as a class, some have been removed from use. Clinafloxacin, fleroxacin, gatifloxacin, grepafloxacin, pefloxacin, sparfloxacin, and trovafloxacin have been withdrawn due to unacceptable side effects such as hepatic toxicity, cardiovascular problems, phototoxicity, and changes in glucose metabolism. Levofloxacin, however, has been shown to be extremely safe and well tolerated. There is extensive clinical data and postmarketing surveillance that clearly demonstrate it to be a safe agent. Concerns about the development of fluoroquinolone side effects have generally resulted in the administration of low to moderate doses. This is not a concern for levofloxacin. There are now reports available confirming it is well tolerated in higher doses. This paper discusses the optimal dosage of levofloxacin, including the use of the new high-dose strategy.

Prof. Wolfgang Graninger, MD, PhD Department of Medicine, Division of Infectious Diseases and Chemotherapy, Internal Medicine, University of Vienna Währinger, Gürtel 18–20, A–1090 Vienna (Austria) Tel. +43 1 40400 4440, Fax +43 1 40400 4418, E-Mail [email protected]

Pharmacologic Rationale for High-Dose Levofloxacin Therapy

Research and clinical experience has shown that highdose fluoroquinolone therapy may be indicated in certain situations. These include overweight patients, who due to their large physical size require higher doses to provide effective therapy. This is illustrated by the case history of a 52-year old man, weighing 100 kg, who developed fever, malaise and migrating pulmonary infiltrates. Initial treatment with amoxicillin-clavulanic acid resulted in no response. Treatment was changed to clarithromycin 500 mg b.i.d. and after no improvement this was changed to levofloxacin 500 mg b.i.d., which resulted in a successful outcome. Culture results confirmed a Legionella infection, which had not been adequately treated by the clarithromycin dose. High-dose levofloxacin therapy proved successful and well tolerated. In addition to large patients, high-dose therapy may be required for patients with serious infections requiring admission to the intensive care unit (ICU). This may be due to changes in the metabolism of seriously ill patients as well as their greater probability of presenting with different pathophysiological conditions that alter the pharmacokinetic (PK) profiles of individual agents. ICU patients are also more likely to have an infection caused by difficult-to-treat pathogens or resistant organisms [1]. The differences in PK parameters for ICU patients, healthy volunteers, and those with lower respiratory tract infections (LRTIs) following levofloxacin administration have been recently reported. Results confirmed that levofloxacin 500 mg b.i.d. achieved an area under the curve (AUC) of 33.90 mg W h/l ! 2 in ICU patients, 49.60 mg W h/l in healthy volunteers, and 74.97 mg W h/l in those with LRTIs. This supports the rationale for administering higher doses of levofloxacin to patients in ICU in order to achieve better pharmacodynamic values predictive of improved clinical outcomes [1].

levofloxacin 500 mg i.v. had a maximum concentration (Cmax) of 7.5 B 0.8 mg/l and AUC from 0 to 24 h (AUC0–24) of 66.1 B 15.7 mg W h/l. Following oral levofloxacin 500 mg, Cmax was 5.5 B 1.1 mg/l, achieved at 1.3 B 0.4 h. These values were significantly different (p ! 0.05) from those noted after parenteral administration, although all other PK parameters were similar. The study concluded that the 500-mg once-daily dosage of levofloxacin appears adequate for most pathogens found in critically ill patients with normal renal function, but higher doses should be considered in situations where less susceptible pathogens such as Enterobacter species are suspected. Further evidence supporting the need for higher doses in ICU patients comes from a recent analysis of 8 patients with sepsis. Antimicrobial therapy of soft tissue infections can be problematic due to poor concentrations at the site of infection in seriously ill patients. A recent report has investigated the impact of tissue penetration of anti-infective agents on bacterial killing [3]. Concentration-versustime profiles were measured by microdialysis in the interstitial fluid of skeletal muscle. Results confirmed that levofloxacin possesses excellent penetration into soft tissues, with a ratio of the AUC from 0 to 8 h (AUC0–8) for muscle tissue to the AUC0–8 for free drug in plasma of 0.85. The individual values of tissue penetration and maximum concentration in muscle tissue were highly variable (fig. 1). Further investigation of bacterial killing rates demonstrated that while the usual 500-mg dose of levofloxacin may be sufficient for Staphylococcus aureus, higher doses may be required for Pseudomonas aeruginosa [3]. Additional pharmacokinetic data has been reported comparing 500, 750 and 1,000 mg levofloxacin o.d. all given for 10 days [4]. Results demonstrated a linear relationship with marked differences in pharmacokinetic features. The Cmax values for the 500-, 750-, and 1,000-mg doses were 5.7, 8.6, and 11.8 mg/l, respectively and the AUC values were 48, 91, 118 mg W h/l, respectively (table 1). Therefore as the dose increased, plasma and tissue levels rose correspondingly.

Use of High-Dose Therapy against Difficult-to-Treat Pathogens Significantly Greater Epithelial Lining Fluid Penetration for Levofloxacin Compared to Ciprofloxacin

Additional data confirming alterations in PK/PD parameters in ICU patients was reported in late 2002 [2]. The prospective, open-label study evaluated the PK profile of levofloxacin following intravenous (i.v.) and oral administration in 28 critically ill adults. Results revealed a mean half-life of 8.0 B 1.7 h and volume of distribution of 1.2 B 0.3 l/kg for all 28 patients. Patients receiving

High-dose therapy was assessed in a double-blind, randomized, placebo-controlled, single-center parallel group study investigating the safety and PK effects of once-daily 750 mg i.v. levofloxacin in 18 healthy volunteers [5].

Levofloxacin for Severe Infections


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Fig. 1. Levofloxacin in septic patients. Adapted from ref. 3.

Table 1. Pharmacokinetic variables

associated with levofloxacin therapy – multiple dose

Multiple dose

Cmax

Tmax (h)

AUC

CL/F

t1/2 (h)

500 mg q.d. ! 10 d 750 mg q.d. ! 10 d 1,000 mg q.d. ! 10 d

5.7B1.4 8.6B1.86 11.8B2.52

1.1B0.4 1.9B0.7 1.7B0.6

48B7 91B18 118B19

175B25 143B29 146B29

7.6B1.6 8.8B1.3 8.9B2.5

For abbreviations, see text. Adapted from ref. 4.

Levofloxacin was well tolerated and higher Cmax and AUC values were achieved. The researchers concluded that higher daily doses of levofloxacin may be beneficial in difficult-to-treat infections and i.v. administration may be recommended in certain clinical settings, such as ICU. An important multiple-dose, open-label, randomized pharmacokinetic study investigated steady-state plasma and lung concentrations of fluoroquinolones in 36 volunteers [6]. Regimens used were 500 mg and 750 mg levofloxacin o.d., and 500 mg ciprofloxacin b.i.d. The mean steady-state concentrations in epithelial lining fluid (ELF) at 12 h for levofloxacin 500 mg was 6.5 B 2.5 mg/l and for levofloxacin 750 mg, 9.2 B 5.3 mg/l. The concentration of ciprofloxacin in ELF at 12 h was 0.4 B 0.1 mg/l. The differences in ELF concentrations of the two levofloxacin

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dosages and ciprofloxacin were significant (p ! 0.05). Levofloxacin achieved more extensive distribution throughout the lung tissue as well as significantly higher steady-state concentrations in plasma and ELF during the 24 h after drug administration (fig. 2) [6].

Clinical Indications for High-Dose Levofloxacin

The pharmacokinetic data presented above support the rationale for using higher dose levofloxacin therapy, particularly in severe infections such as nosocomial pneumonia or those with difficult pathogens such as Klebsiella pneumoniae.

Graninger/Zeitlinger

Fig. 2. Concentrations of ciprofloxacin and

levofloxacin in ELF. Adapted from ref. 6.

A large multicenter, prospective, randomized, openlabel trial compared levofloxacin 750 mg i.v. o.d. followed by oral administration for 7–15 days or imipenem/cilastatin 500–1,000 mg i.v. every 6–8 h, followed by oral ciprofloxacin 750 mg every 12 h for 7–15 days [7]. The primary endpoint was clinical response in microbiologically evaluable patients 3–15 days after the end of therapy. A total of 438 patients were enrolled in the study; 220 received levofloxacin and 218 received the alternative regimen. Patient characteristics were similar for both groups. Clinical success rates were 58.1% in the levofloxacin group compared with 60.6% in the other group. In the 187 patients evaluable for microbiologic efficacy, eradication was achieved in 66.7% of patients receiving levofloxacin and 60.6% of imipenem/cilastatin patients. This confirmed that in these very difficult-to-treat patients with other co-morbidities, levofloxacin 750 mg o.d. was equivalent to imipenem/ ilastatin 500–1,000 mg t.i.d., followed by oral ciprofloxacin 750 mg b.i.d. The 750 mg levofloxacin regimen was also well tolerated and the incidence of all reported adverse drug reactions (ADRs) was less than 5% [7]. Levofloxacin 750 mg o.d. may be useful in other infections, including complicated skin and skin structure infections (CSSSIs), as it is able to achieve higher concentrations in wound tissue than in blood [8]. A study investigating antimicrobial concentrations in patients undergoing bone surgery who received levofloxacin as perioperative prophylaxis has been reported. Samples were taken approximately 1.5 h after drug administration. The mean

serum concentration was 8.6 B 2.3 mg/l, with all concentrations above the minimal inhibitory concentration (MIC) of common pathogens. The highest levels were recorded in skin (19.9 mg/l), followed by wound tissue (17.3 mg/l) and granulation tissue (13.7 mg/l). Levofloxacin concentrations in muscle and fatty tissue were 8.0 and 4.0 mg/l, respectively. The lowest levels were found in cancellous bone (6.6 mg/l) and cortical bone (2.8 mg/l) (fig. 3). A recent study compared 750 mg levofloxacin with ticarcillin-clavulanic acid (TC) 3.1 g q.i.d. followed by amoxicillin-clavulanic acid (AC) 875 mg b.i.d. at the investigator’s discretion for the treatment of CSSSIs in 399 patients. The clinical success rate for levofloxacin was 84.1% and for the TC/AC arm, 80.3% [9]. Microbiological success with levofloxacin was also higher at 83.7% compared with 71.4% for TC/AC. Levofloxacin was effective in treating a wide range of difficult pathogens including Pseudomonas aeruginosa, S. aureus and Enterococcus faecalis (table 2). This data demonstrates that levofloxacin 750 mg o.d. is safe and at least as effective as TC/AC for CSSSIs.



Conclusions

Fluoroquinolones remain the drug of choice in severe infections and are used widely for CAP and chronic obstructive pulmonary disease (COPD), nosocomial

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Fig. 3. Mean levofloxacin concentrations + SD in serum and tissue samples after 500 mg o.d. Adapted from ref. 8.

Table 2. Clinical success rates according to pathogens isolated

Staphylococcus aureus Streptococcus agalactiae Enterococcus faecalis Proteus mirabilis Pseudomonas aeruginosa Others

Levofloxacin

Ticarcillin-clavulanic acid/ amoxicillin-clavulanic acid

48/55 8/12 9/11 9/10 6/7 24/33

39/50 9/14 9/12 7/12 6/6 15/20

84%

71%

preferable to use a higher dose of 750 mg. This dose has been used safely in a number of patients and data supporting its efficacy and tolerability are steadily growing. With the 750-mg dose, and even at higher doses of 1,000 mg/ day, levofloxacin appears to be safe with an overall low incidence of side effects.

Adapted from ref. 9.

pneumonia, legionellosis, nosocomial sepsis, and intraabdominal infections. They are also indicated in some cases of pyelonephritis, prostatitis, epididymitis, typhoid fever, osteomyelitis, and diabetic foot infections. Highdose levofloxacin therapy may also extend this list of indications by having a role in managing ventilator-associated pneumonia (VAP), severe CAP, especially with the aim of shortening the duration of therapy, and P. aeruginosa infection. Therefore, while the normal dosage of levofloxacin is 500 mg o.d., in certain clinical situations it may be

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Graninger/Zeitlinger

References 1 Viale P, Pea F: What is the role of fluoroquinolones in intensive care? J Chemother 2003; 15(suppl 3):5–10. 2 Rebuck JA, Fish DN, Abraham E: Pharmacokinetics of intravenous and oral levofloxacin in critically ill adults in a medical intensive care unit. Pharmacotherapy 2002;22:1216–1225. 3 Zeitlinger MA, Dehghanyar P, Mayer BX, Schenk BS, Neckel U, Heinz G, Georgopoulos A, Muller M, Joukhadar C: Relevance of softtissue penetration by levofloxacin for target site bacterial killing in patients with sepsis. Antimicrob Agents Chemother 2003;47:3548–3553. 4 Wimer SM, Schoonover L, Garrison MW: Levofloxacin: a therapeutic review. Clin Ther 1998;20:1049–1070.


5 Chow AT, Fowler C, Williams RR, Morgan N, Kaminski S, Natarajan J: Safety and pharmacokinetics of multiple 750-milligram doses of intravenous levofloxacin in healthy volunteers. Antimicrob Agents Chemother 2001;45:2122– 2125. 6 Gotfried MH, Danziger LH, Rodvold KA: Steady-state plasma and intrapulmonary concentrations of levofloxacin and ciprofloxacin in healthy adult subjects. Chest 2001;119:1114– 1122. 7 West M, Boulanger BR, Fogarty C, Tennenberg A, Wiesinger B, Oross M, Wu SC, Fowler C, Morgan N, Kahn JB: Levofloxacin compared with imipenem/cilastatin followed by ciprofloxacin in adult patients with nosocomial pneumonia: a multicenter, prospective, randomized, open-label study. Clin Ther 2003;25: 485–506.

8 von Baum H, Bottcher S, Abel R, Gerner HJ, Sonntag HG: Tissue and serum concentrations of levofloxacin in orthopaedic patients. Int J Antimicrob Agents 2001;18:335–340. 9 Graham DR, Talan DA, Nichols RL, Lucasti C, Corrado M, Morgan N, Fowler CL: Oncedaily, high-dose levofloxacin versus ticarcillinclavulanate alone or followed by amoxicillinclavulanate for complicated skin and skinstructure infections: a randomized, open-label trial. Clin Infect Dis 2002;35:381–389.


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New Insights in the Treatment by Levofloxacin Thomas M. File Jr. Infectious Disease Service, Summa Health System, Akron, Ohio, and Northeastern Ohio Universities College of Medicine, Rootstown, Ohio, USA

Key Words Levofloxacin W Fluoroquinolones W Community-acquired pneumonia W Respiratory infection W High-dose therapy W Safety

Abstract Levofloxacin is widely regarded as one of the most important fluoroquinolones available today. It possesses excellent activity against a wide range of important pathogens, including those resistant to many other antimicrobials. While rates of resistance to other previously useful antimicrobial classes has grown, levofloxacin has maintained its efficacy, with generally very low rates of resistance around the world. It is indicated for a wide range of infections including community-acquired respiratory infections in adults, particularly community-acquired pneumonia (CAP), acute bacterial exacerbations of chronic bronchitis (AECB), and acute sinusitis. In addition, it is recommended for infections of skin and soft tissue, and the urinary tract. With postmarketing surveillance data available for the last decade, levofloxacin possesses an unparalleled database to demonstrate its clinical efficacy and safety. Remarkably, levofloxacin continues to expand its list of indications. The development of a new high-dose 750-mg schedule has the potential to decrease the duration of treatment as well as reduce the emergence of resistance.

Introduction

Levofloxacin was among the first of the fluoroquinolones to be successfully marketed which has good antipneumococcal activity. It has been available in Japan since 1993 and in the US since 1997. It has been used in more than 300 million prescriptions with minimal emergence of resistance. The extensive clinical database available on levofloxacin has proven it to be a safe and effective agent with excellent bactericidal activity against a range of key pathogens. These include Streptococcus pneumoniae, including drug-resistant S. pneumoniae (DRSP), Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae, Chlamydia pneumoniae and Legionella pneumophila. In addition it has coverage against Enterobacteriaceae, approximately 60–65% of Pseudomonas aeruginosa and methicillin-susceptible Staphylococcus aureus (MSSA). This spectrum of activity makes levofloxacin a very attractive agent for the management of community-acquired respiratory tract infections (RTIs). It has excellent penetration into both intra- and extracellular tissues, which provide it with activity against the intracellular pathogen Legionella. Like any class of antibiotic, fluoroquinolones can be subject to overuse. It is therefore important that they be prescribed judiciously in order to maintain their excellent clinical utility. This paper reviews the latest insights into the most appropriate use of the fluoroquinolone levofloxacin.

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Prof. Thomas M. File, Jr., MD, MS Department of Internal Medicine, Summa Health System 75 Arch Street, Suite 105, Akron, OH 44304 (USA) Tel. +1 330 375 3894, Fax +1 330 375 3161 E-Mail [email protected]

Clinical Indications for Levofloxacin

Levofloxacin is indicated for the treatment of community-acquired pneumonia (CAP), sinusitis, acute bacterial exacerbations of chronic bronchitis (AECB), nosocomial pneumonia, skin infections, and urinary tract infections. In addition, recent additional indications include the use of a 750-mg dose for CAP, allowing a shorter five-day regimen, and complicated skin and soft structure infections (CSSSIs), as well as a 500-mg dose to treat chronic bacterial prostatitis. There is extensive clinical data available confirming the excellent activity of levofloxacin in the management of CAP. An important clinical trial in 1997 compared levofloxacin to the prevailing standard, ceftriaxone, with or without a macrolide. It found that the clinical response for levofloxacin was 96% compared to 90% for the comparator. The bacteriological response was 98% for levofloxacin and 85% for the comparator. Levofloxacin achieved significantly better responses than the comparator in terms of both clinical and bacteriological endpoints [1]. The efficacy of fluoroquinolones in CAP was subsequently confirmed in a large study comparing moxifloxacin and a ß-lactam (amoxicillin-clavulanic acid IV with or without clarithromycin), the fluoroquinolone regimen again being significantly better than the comparator [2]. Recent reports have reinforced the usefulness of levofloxacin in CAP [3–5]. A large, multicentre phase-IV trial evaluated 1,730 patients receiving levofloxacin for CAP in the intention-to-treat analysis [3]. A pathogen was identified in 24% of patients, comprising Streptococcus pneumoniae (64%), Haemophilus influenzae (21%) and, interestingly, the third most commonly identified pathogen was Staphylococcus aureus (16%). Clinical success was achieved in 94% of patients, bacteriological eradication in 95.6 and 100% of drug-resistant S. pneumoniae (DRSP) isolates were eradicated. The rate of drug-related adverse events (AEs) was 4.5%. Nausea was reported in 0.9% of patients, and rash and diarrhea in 0.5%. The researchers concluded that results from this large study confirm levofloxacin to be safe and effective in the treatment of CAP. Another important study is the first published report comparing monotherapy with a fluoroquinolone versus combination therapy in severe CAP. The study compared 95 patients treated with levofloxacin monotherapy to 89 administered ceftriaxone plus erythromycin. All patients met either of the following criteria for severe CAP: (1) More than three American Thoracic Society (ATS) criteria or the use of a ventilator. (2) More than two of the following criteria: respiratory rate 130 breaths/min, pulse

New Insights for Levofloxacin

rate 1130 beats/min, systolic blood pressure !90 mm Hg, mental status changes, temperature 138 ° C or !35.5 ° C. The clinical response rate for levofloxacin monotherapy was 89% and for the ceftriaxone/erythromycin group 83% [4]. The bacteriological response rate for levofloxacin was 87.7%, compared to 81% for the combination regimen. Adding to this data are results from a study reported in 2004, which reviewed an important subgroup of patients with CAP-associated pneumococcal bacteremia. Analysis of results from nine clinical trials compared 108 bacteremic pneumococcal pneumonia patients treated with levofloxacin monotherapy versus a comparator [5]. This is an important trial because it has recently been suggested that pneumonia patients with pneumococcal bacteremia treated with a ß-lactam and macrolide do better than with a ß-lactam alone. Therefore there is a trend toward combination therapy, but the use of a fluoroquinolone such as levofloxacin may show this to be unnecessary. Results demonstrated that levofloxacin monotherapy had a 91% clinical response rate (92% for infections caused by DRSP). The researchers concluded that levofloxacin monotherapy was comparable to combination therapy. In addition to being effective, levofloxacin has extremely high (99%) oral bioavailability, allowing oral therapy to be administered as initial treatment for many patients who previously would have required parenteral therapy. Two studies looking at monotherapy with a fluoroquinolone versus parenteral therapy in inpatients have confirmed comparable results for oral fluoroquinolones versus intravenous (i.v.) ceftriaxone (with or without a macrolide) [6, 7]. Of further benefit is the ease by which fluoroquinolones can be switched from parenteral to oral therapy, which is associated with significant cost savings. This is confirmed in a study comparing levofloxacin vs. ceftriaxone, that demonstrated i.v. to oral switch therapy with levofloxacin was more cost-effective than ceftriaxone in patients hospitalized with CAP [8].

Summary of CAP Guidelines

Fluoroquinolones are now listed prominently as treatment options for both outpatients and inpatients with CAP [9–11]. Recent Infectious Diseases Society of America (IDSA) guidelines recommend fluoroquinolones in previously well outpatients who have been treated with another class of antibiotics within the past 3 months, due to concerns about drug resistance, and also for those patients with comorbid diseases such as diabetes, chronic


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Table 1. Community-acquired pneumonia:

empiric therapy – IDSA 2003

General ward inpatients Respiratory fluoroquinolone; ß-lactama + macrolide ICU inpatients No Risk for Pseudomonas c ß-lactama + [macrolide or respiratory fluoroquinolone] Anti-pneumococcal/pseudomonal ß-lactamb + ciprofloxacin Risk for Pseudomonas c (Alter: Levofloxacin + aztreonam +/– aminoglycoside) a b c

Cefotaxime, ceftriaxone, ampicillan-sulbactum, ertapenem. Piperacillin; imipenem; meropenem; cefepime. Bronchiectasis, recent ATB or prior hospitalization in ICU.

obstructive pulmonary disease (COPD), congestive heart failure, renal insufficiency, or cancer. In patients who require admission to hospital, IDSA guidelines state that respiratory fluoroquinolones are an appropriate monotherapy on the general ward. For intensive care unit (ICU) patients with no risk of pseudomonal infection, the combination of a ß-lactam (e.g. ceftriaxone or cefotaxime) plus an i.v. macrolide or fluoroquinolones is recommended. However, when a Pseudomonal aeruginosa infection is suspected, fluoroquinolones should be administered in combination therapy with an anti-pseudomonal ß-lactam (table 1). In this situation it is also recommended that the 750-mg dose of levofloxacin be used [12]. Other recent guidelines include those from the Canadian Medical Association, which recommends fluoroquinolones for complicated AECB, and the Allergy and Sinus Partnership’s most recent 2004 recommendations include fluoroquinolones for moderate sinusitis or in those who have been treated with an agent in the recent past. The available international guidelines reflect the importance of fluoroquinolones as therapeutic options for CAP around the world, with Latin America, Japan, the UK and North America advocating the use of fluoroquinolones in specific patients with CAP.

Resistance to Other Antimicrobials Resulting in Greater Fluoroquinolone Use

One of the common themes in the therapeutic guidelines is the need to use fluoroquinolones when a patient has been unsuccessfully treated with another class of antimicrobials. The most recent surveillance data from the TRUST VII data (isolates from 2002–2003 northern winter months) confirmed that resistance to levofloxacin in the US has remained below 1% in most areas (0.9%). There has also been no slow rise in the minimal inhibitory

24


concentration (MIC) values over time. This is confirmed by other surveillance studies such as PROTEKT 2000– 2001, which reported a levofloxacin resistance rate of 0.8%. Although there are some areas with slightly higher resistance rates, including Canada (4%), this does not reflect the general trend for low resistance rates. As with all antibiotics it is important for the physician to ask about prior treatment and if the patient has received a fluoroquinolone within the past 3 months, another class of agent should be recommended. Risk factors associated with levofloxacin resistance include prior use, extracellular fluid and COPD [13]. A review of all of the major surveillance studies including the North American TRUST study, SENTRY trial and PROTEKT show the rates of levofloxacin resistance to be extremely low and stable apart from one well-known clone in Hong Kong [13–18].

New Indications for Levofloxacin

A recent study by Bundrick has been used to support the indication of levofloxacin for treating chronic bacterial prostatitis. Levofloxacin 500 mg o.d. was administered to 136 patients and compared to ciprofloxacin 500 mg b.i.d. in 125 patients. Clinical success with levofloxacin was 75.0% compared to 72.8% for ciprofloxacin. Bacteriological eradication rates were also comparable with levofloxacin achieving rates of 75.0% and ciprofloxacin 76.8%. Another indication is that of high-dose therapy using a 750 mg levofloxacin schedule. The rationale for this dose is based upon the ability to maximize concentrationdependent killing, with increased bactericidal activity, allowing treatment of difficult pathogens, increased penetration into various tissues and fluids, the potential to prevent the emergence of resistance, and possible provision of a shorter course therapeutic schedule and more rapid

File

resolution of symptoms. The 750-mg dose achieves higher Cmax/MIC90 ratios of 11.5 compared to 6.2 for the 500-mg dose. In addition AUC/MIC90 values increase from 48 with the 500-mg dose to 110 with the 750-mg dose. These factors are known to be important pharmacodynamic predictors of outcome or pathogen eradication and as such they indicate that the higher dose strategy is likely to result in improved clinical results for difficult-to-treat pathogens. However, one of the issues to be considered when advocating the 750-mg dose is safety. Clinical studies have now been performed to address this issue. The high-dose strategy is advocated in a number of clinical situations, including nosocomial pneumonia, with 750 mg levofloxacin given o.d. for 7–15 days compared with imipenem/cilastatin 500/1,000 mg, q 6–8 h for 7–15 days [19]. Where there was concern regarding a potential pseudomonas infection, double-drug therapy was administered, adding ceftazidime to the levofloxacin arm and amikacin to the imipenem/cilastatin group. There were 118 clinically evaluable patients in the levofloxacin arm and 63 in the comparator arm. Results were equivalent for both study arms with clinical success rates of 59 and 63% respectively, and a 67% bacteriological eradication rate for levofloxacin compared to 61% for imipenem/cilastatin. In addition it is advocated in the treatment of serious skin infections and has been compared with ticarcillin– clavulanic acid [20]. The response rate was comparable for both treatment arms (84% for levofloxacin and 80% for ticarcillin-clavulanic acid), but the levofloxacin arm had a statistically significantly better bacterial eradication rate (87 vs. 73%) and this was of particular note against S. aureus (table 2).

Table 2. Levofloxacin 750 mg q.d. versus ticarcillin-clavulanic acid

for treatment of serious skin infections

Diagnosis (clinical response) Major abscess Wound infections Other Diabetic ulcers Total Key pathogens (eradication) Staphylococcus aureus Streptococcus agalactiae Gram-negative aerobes Total

Levofloxacin (%)

Ticarcillin-clavulanic acid (%)

36/40 (90) 47/53 (89) 15/19 (79) 18/26 (69) 84

36/40 (90) 41/48 (85) 13/16 (81) 16/28 (57) 80

50/56 (89) 9/12 (75) 37/44 (84) 87

35/49 (71)* 9/13 (69) 31/45 (69) 73*

* Significant. Adapted from ref. 20.

A recent multicentre, double-blind study compared 750 mg levofloxacin in a short five-day therapy schedule to 500 mg levofloxacin for the usual 10 days [21]. There were 198 evaluable patients in the levofloxacin 750 mg arm and 192 in the 500 mg arm. The overall clinical success rate for the high-dose group was 92.4% compared to 91.1% for the 500 mg longer course treatment (table 3). When patients were analyzed according to severity of illness, using the pneumonia severity index (PSI), it was shown that the 750 mg five-day course achieved similar clinical response rates. Even when response was evaluated according to pathogen, it was shown that the short-course

therapy achieved high success rates; Chlamydia pneumoniae (90.9%), Legionella pneumophila (100%) and Mycoplasma pneumoniae (95.3%) (table 4). Therefore in immunocompetent patients, short-course therapy was effective even for serious pathogens such as Legionella. Of great interest were results showing that high-dose, short-course therapy was significantly more likely to result in more rapid resolution of fever, as assessed both by the patient and researcher in this double-blind study (table 5) [22]. In addition, there was a trend for greater resolution of purulent sputum, which may be related to more rapid eradication of the pathogens, resulting in more rapid symptom resolution. Patients in the 750 mg arm also had a quicker transition from parenteral to oral therapy, with 42% of the 750 mg group switching to oral therapy by day 2, compared to only 38% of the 500 mg group. By day 3, 68% of the 750 mg group had started oral therapy compared to 61% of the 500 mg arm. Overall, the median days of parenteral therapy in the high-dose schedule was 2.35 compared to 2.75 for the longer course therapy (p = 0.098). This more rapid transition to oral therapy for the 750-mg dose may translate into a decreased length of hospital stay. Although proven effective and potentially allowing shorter therapy, the issue to be clarified is whether the higher dose is safe. Results from the Graham study confirmed that the 750-mg dose was as well tolerated as the 500-mg dose (table 6). Not only was the high dose as effective, but it was also as well tolerated as the 500-mg dose, with no increase in drug-related AEs.



High-Dose, Short-Course Levofloxacin Therapy for CAP

25

Table 3. 750 mg, short-course levofloxacin

n/N of patientsa

for CAP: clinical success rates*

All patients Stratum I PSI Class III/IV/V combined PSI Class III PSI Class IV PSI Class V Stratum II PSI Class I/II combined

750 mg 5 days (N = 198)

500 mg 10 days (N = 192)

95% CI

183/198 (92.4)

175/192 (91.1)

(–7.0, 4.4)

69/76 (90.8) 44/49 (89.8) 25/27 (92.6) 0/0 (0.0)

73/86 (84.9) 44/51 (86.3) 27/32 (84.4) 2/3 (66.7)

114/122 (93.4)

102/106 (96.2)

(–16.5, 4.7) (–17.2, 10.2) (–26.1, 9.6) na (–3.4, 9.0)

* Clinically evaluable population at the test-of-cure visit. Percentages based on total number of patients for the stratum or risk class and treatment. Adapted from ref. 21. For abbreviations, see text. a


n/N (%) of patientsa

for CAP: clinical success by pathogen* Source/pathogen Respiratory cultures (typical pathogens) H. influenzae H. parainfluenzae S. pneumoniae Serologies (atypical pathogens) C. pneumoniae L. pneumophila M. pneumoniae

750 mg

500 mg

12/13 (92.3) 12/12 (100) 20/22 (90.9)

13/14 (92.9) 9/10 (90.0) 18/20 (90.0)

20/22 (90.9) 11/11 (100) 41/43 (95.3)

16/16 (100) 3/3 (100) 34/36 (94.4)

* Identified in at least 5 clinically evaluable patients at the 7- to 14-day post-therapy visit. a Numbers shown in parentheses are percentages of patients infected with the pathogen who had a clinical response of cure or improvement, divided by total number of patients infected with the pathogen. Adapted from ref. 21.


n/N (%) of patients

for CAP: Symptom resolution at 3 days

Fever (patient reported) Fever (measured) Purulent sputum Shortness of breath Pleuritic chest pain Chills Cough

750 mg

500 mg

p value*

161/239 (67.4) 111/226 (49.1) 97/239 (40.6) 84/239 (35.1) 72/239 (30.1) 131/239 (54.8) 24/239 (10.0)

130/238 (54.6) 89/231 (38.5) 73/238 (30.7) 66/238 (27.7) 65/238 (27.3) 129/238 (54.2) 24/238 (10.1)

0.006 0.027 0.059 0.132 0.532 0.901 0.990

* p value was determined from two-sample McNemar’s test. Adapted from ref. 22.

26


File

Table 6. Levofloxacin: treatment – emergent adverse events

Respiratory insufficiency Diarrhea Constipation Nausea Condition aggravated Skin disorder Sepsis Agitation Insomnia Headache Anemia Hypotension

Phase III: 250/500 mg (%)

CSSS 750 mg (%)

0.2 5.5 2.9 7.2 0.2 0.4 0.1 0.5 4.3 5.3 0.1 0.2

0.0 3.0 5.0 5.0 1.0 0.0 0.5 1.5 6.0 4.0 1.5 1.0

Conclusion

Levofloxacin has an unsurpassed safety record coupled with exceptional activity against both Gram-positive and Gram-negative pathogens. With almost 100% bioavailability it can be used as an oral agent. Due to its advantageous pharmacokinetic and pharmacodynamic profile it can be administered in an effective once-daily schedule. Levofloxacin offers the physician a unique antimicrobial with indications now being extended to encompass a high-dose, short-course therapy to manage difficult-totreat pathogens. It has the potential to further improve efficacy and safety, and minimize resistance, making it an attractive future therapeutic option.

Adapted from ref. 20.

References 1 File TM Jr, Segreti J, Dunbar L, Player R, Kohler R, Williams RR, Kojak C, Rubin A: A multicenter, randomized study comparing the efficacy and safety of intravenous and/or oral levofloxacin versus ceftriaxone and/or cefuroxime axetil in treatment of adults with community-acquired pneumonia. Antimicrob Agents Chemother 1997;41:1965–1972. 2 Finch R, Schurmann D, Collins O, Kubin R, McGivern J, Bobbaers H, Izquierdo JL, Nikolaides P, Ogundare F, Raz R, Zuck P, Hoeffken G: Randomized controlled trial of sequential intravenous (i.v.) and oral moxifloxacin compared with sequential i.v. and oral co-amoxiclav with or without clarithromycin in patients with community-acquired pneumonia requiring initial parenteral treatment. Antimicrob Agents Chemother 2002;46:1746–1754. 3 Akpunonu B, Michaelis J, Uy CN, Tennenberg AM, Wiesinger BA, Karim R, Marshall JS, Kahn JB: Multicenter, postmarketing assessment of levofloxacin in the treatment of adults with community-acquired pneumonia. Clin Infect Dis 2004:38(suppl 1):S5–S15. 4 Fogarty C, Siami G, Kohler R, File TM Jr, Tennenberg AM, Olson WH, Wiesinger BA, Marshall JS, Oross M, Kahn JB: Multicenter, openlabel, randomized study to compare the safety and efficacy of levofloxacin versus ceftriaxone sodium and erythromycin followed by clarithromycin and amoxicillin-clavulanate in the treatment of serious community-acquired pneumonia in adults. Clin Infect Dis 2004: 38(suppl 1):S16–S23.


5 Kahn JB, Bahal N, Wiesinger BA, Xiang J: Cumulative clinical trial experience with levofloxacin for patients with community-acquired pneumonia-associated pneumococcal bacteremia. Clin Infect Dis 2004:38(suppl 1):S34– S42. 6 Lode H, File TM Jr, Mandell L, Ball P, Pypstra R, Thomas M: 185 Gemifloxacin Study Group: Oral gemifloxacin versus sequential therapy with intravenous ceftriaxone/oral cefuroxime with or without a macrolide in the treatment of patients hospitalized with community-acquired pneumonia: a randomized, open-label, multicenter study of clinical efficacy and tolerability. Clin Ther 2002;24:1915–1936. 7 Soemantri ES et al: Poster presented at the 10th International Congress on Infectious Diseases; March 11–14, 2002, Singapore. Abstract 62.011. 8 Mangunnegoro H et al: Preliminary findings presented at the Expert Meeting on Practice Guidelines for the Management of CAP in Asia; October 11, 2002, Thailand. 9 Mandell LA, Bartlett JG, Dowell SF, File TM Jr, Musher DM, Whitney C: Infectious Diseases Society of America: Update of practice guidelines for the management of communityacquired pneumonia in immunocompetent adults. Clin Infect Dis 2003;37:1405–1433. 10 Balter MS, La Forge J, Low DE, Mandell L, Grossman RF, Canadian Thoracic Society, Canadian Infectious Disease Society: Canadian guidelines for the management of acute exacerbations of chronic bronchitis. Can Respir J 2003;10(suppl B):3B–32B.

11 Anon JB, Jacobs MR, Poole MD, Ambrose PG, Benninger MS, Hadley JA, Craig WA: Sinus and allergy health partnership: Antimicrobial treatment guidelines for acute bacterial rhinosinusitis. Otolaryngol Head Neck Surg 2004; 130(1 suppl):1–45. 12 Mandell LA, Bartlett JG, Dowell SF, File TM Jr, Musher DM, Whitney C, Infectious Diseases Society of America: Update of practice guidelines for the management of communityacquired pneumonia in immunocompetent adults. Clin Infect Dis 2003;37:1405–1433. 13 Ho PL, Tse WS, Tsang KW, Kwok TK, Ng TK, Cheng VC, Chan RM: Risk factors for acquisition of levofloxacin-resistant Streptococcus pneumoniae: a case-control study. Clin Infect Dis 2001;32:701–707. 14 Karlowsky JA, Thornsberry C, Jones ME, Evangelista AT, Critchley IA, Sahm DF, TRUST Surveillance Program: Factors associated with relative rates of antimicrobial resistance among Streptococcus pneumoniae in the United States: results from the TRUST Surveillance Program (1998–2002). Clin Infect Dis 2003;36:963–970. 15 Jones RN, Pfaller MA: Macrolide and fluoroquinolone (levofloxacin) resistances among Streptococcus pneumoniae strains: significant trends from the SENTRY Antimicrobial Surveillance Program (North America, 1997– 1999). J Clin Microbiol 2000;38:4298–4299. 16 Sahm DF, Jones ME, Hickey ML, Diakun DR, Mani SV, Thornsberry C: Resistance surveillance of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis isolated in Asia and Europe, 1997–1998. J Antimicrob Chemother 2000;45:457–466.


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17 Ho PL, Que TL, Tsang DN, Ng TK, Chow KH, Seto WH: Emergence of fluoroquinolone resistance among multiply resistant strains of Streptococcus pneumoniae in Hong Kong. Antimicrob Agents Chemother 1999;43:1310–1313. 18 Ho PL, Yung RW, Tsang DN, Que TL, Ho M, Seto WH, Ng TK, Yam WC, Ng WW: Increasing resistance of Streptococcus pneumoniae to fluoroquinolones: results of a Hong Kong multicentre study in 2000. J Antimicrob Chemother 2001;48:659–665.

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19 West M, Boulanger BR, Fogarty C, Tennenberg A, Wiesinger B, Oross M, Wu SC, Fowler C, Morgan N, Kahn JB: Levofloxacin compared with imipenem/cilastatin followed by ciprofloxacin in adult patients with nosocomial pneumonia: a multicenter, prospective, randomized, open-label study. Clin Ther 2003;25: 485–506. 20 Graham DR, Talan DA, Nichols RL, Lucasti C, Corrado M, Morgan N, Fowler CL: Oncedaily, high-dose levofloxacin versus ticarcillinclavulanate alone or followed by amoxicillinclavulanate for complicated skin and skinstructure infections: a randomized, open-label trial. Clin Infect Dis 2002;35:381–389.


21 Dunbar LM, Wunderink RG, Habib MP, Smith LG, Tennenberg AM, Khashab MM, Wiesinger BA, Xiang JX, Zadeikis N, Kahn JB: High-dose, short-course levofloxacin for community-acquired pneumonia: a new treatment paradigm. Clin Infect Dis 2003;37:752–760. 22 Tennenberg A et al: Paper presented at the 99th International Conference of the ATS; 2003, Seattle, Washington.

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