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Highlights from the 21st International Congress of Chemotherapy
Birmingham, UK, July 4-7, 1999

CONTENTS

Introduction

Resistance Mechanism Further Defined

Proven Efficacy in RTIs

Levofloxacin, the Safest New Fluoroquinolone

Improved Pharmacological Features for Levofloxacin Compared to Ciprofloxacin

Levofloxacin - Effective against All S. pneumoniae

Latest Surveillance Data Reported - Safety of Levofloxacin Confirmed

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Introduction

image1The latest International Congress of Chemotherapy (ICC) meeting, a premier event in the field of infectious diseases, provided participants with a forum in which they could discuss the most important issues facing infectious disease physicians now and in the next century. One of the most interesting symposia looked at the role of respiratory fluoroquinolones in the treatment of pneumococcal infection, providing an excellent overview of both preclinical and clinical issues. Although Streptococcus pneumoniae has always been one of the most prevalent respiratory tract pathogens, its significance has increased even further with the widespread rise in resistance. Thus, the development of the improved "respiratory" fluoroquinolones offers the beleaguered infectious disease specialist an extremely useful weapon in their fight against this pathogen.

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Chaired by Dr. Ethan Rubinstein, Tel Aviv University, Tel-Hashomer, Israel, and Dr. William Craig, University of Wisconsin Medical School, Madison, WI, USA, this very timely and important symposium focused upon the role of levofloxacin in the treatment of pneumococcal infections. This symposium began with a presentation by Dr. George Drusano, Albany Medical College, Albany, NY, USA, reporting preclinical data which demonstrated that levofloxacin is very effective given in a once-daily schedule. He reported results from a prospective, multicenter study which determined the pharmacodynamic relationships between measures of levofloxacin exposure and measures of patient outcome. Dr. Drusano found that a peak:MIC ratio greater than 12:1 had a 96% probability of achieving a good clinical outcome in RTI patients. The same breakpoint was chosen for microbiological outcome, and at this level, patients had a 97% chance of achieving a good clinical outcome. This high peak:MIC ratio which levofloxacin achieves is critical in terms of suppressing the development of resistance. The advantageous pharmacodynamic features of levofloxacin have been further validated by recent reports from Dr. Lacy and Dr. Nightingale. They demonstrated that levofloxacin, when given in clinically-appropriate doses, was able to achieve rapid bacterial sterilization within 12 hours. In contrast, ciprofloxacin was associated with a 2.5-3 log drop, but then returned toward baseline following continued dosing due to emergence of resistant mutants (Figure 1). Thus, resistance may be less likely to develop with levofloxacin than ciprofloxacin.

Figure 1. Comparative bactericidal activity for ampicillin, ciprofloxacin, and levofloxacin
Figure_1
Abbreviation : CFU = colony forming unit.
Adapted from Lacy MK, et al. Antimicrob Agents Chemother 43 ; 672-7 : 1999, with the permission of the American Society for Microbiology.

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Resistance Mechanism Further Defined

The mechanism underlying the development of quinolone resistance continued to be "teased out" with Dr. Patrice Courvalin, Institut Pasteur, Paris, France, reporting on the latest understanding into this phenomenon. Fluoroquinolones primarily work by targeting the bacterial enzyme DNA gyrase, either the type II DNA topoisomerase gyrase (DNA gyrase) or the topoisomerase IV (topo IV). Research to determine the primary target of fluoroquinolone resistance in S. pneumoniae has revealed that levofloxacin selects for par C mutants, indicating that its primary target is topo IV. In contrast, the primary target of sparfloxacin and gatifloxacin is the DNA gyrase. Another mechanism of resistance is that of efflux, where hydrophilic quinolones are actively pumped out of the bacteria. This is mediated by a membrane-associated protein, pneumococcal multidrug resistance (pmrA). No differences between the susceptible and resistant strains were noted in regard to the efflux pump, indicating this is due to mutations in regulatory genes, distinct from the pump, which then activate the pump. Dr. Courvalin showed that even susceptible strains vary in their selectivity for pump inhibitors, showing that efflux contributes to the basal level of resistance and is turned on even in susceptible bacteria.

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Proven Efficacy in RTIs

With the compelling pharmacological features of levofloxacin defined, it was then time for Dr. Pramod Shah, University Hospital, Frankfurt, Germany, to review studies assessing its clinical efficacy in treating respiratory tract infections (RTIs). A number of studies have evaluated levofloxacin in the treatment of community-acquired pneumonia (CAP). Dr. File et al. compared levofloxacin and ceftriaxone with both agents used for a similar duration. The cure rates were similar for both antibiotics. One of the latest reports has evaluated levofloxacin 500 mg b.i.d. versus amoxicillin 1,000 t.i.d., and found that levofloxacin was clearly as effective. This study also demonstrated that levofloxacin achieved a 95% eradication rate of S. pneumoniae. A meta-analysis of 13 studies also indicated that levofloxacin is active against penicillin-resistant S. pneumoniae (PRSP).

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Levofloxacin, the Safest New Fluoroquinolone

In a comparative safety review, Dr. Chuen Yee, Robert Wood Johnson Pharmaceutical Research Institute, Raritan, NJ, USA, reported that levofloxacin was safer than grepafloxacin, sparfloxacin and trovafloxacin. Trovafloxacin in particular was shown to be less safe, being recently withdrawn from use due to hepatotoxicity. While the most commonly reported drug reaction with these agents affect the gastrointestinal (GI) system (nausea and diarrhea), even in this situation levofloxacin was better tolerated (Figure 2).

Figure 2. Incidence of drug-related gastrointestinal adverse events from clinical trials.
Figure_2

Sparfloxacin has been associated with phototoxicity and QTc prolongation, trovafloxacin has been associated with hepatotoxicity, and grepafloxacin has been associated with theophylline interaction and QTc prolongation. In contrast, no such problems have been reported with levofloxacin, making it one of the safest of the new fluoroquinolones available on the market.

In order for clinicians to make the most appropriate therapeutic decisions, it is imperative that they have reliable epidemiological information, outlining the most likely causative pathogens in their respective areas. To allow this to happen, surveillance studies have been undertaken assessing the incidence of resistance among different countries. One such international study was performed by Dr. Clyde Thornsberry, MRL Pharmaceutical Services, Brentwood, TN, USA, who evaluated resistances among three pathogens (S. pneumoniae, Moraxella catarrhalis and Haemophilus influenzae). In regard to S. pneumoniae, penicillin-intermediate resistant strains ranged from 7.8% in Germany to 66.5% in France (mean 32.8%). There were no vancomycin-resistant strains and only very rarely levofloxacin-resistant strains. In regard to H. influenzae, ß-lactamase-positive cultures ranged from 5.7% in Germany to 34.5% in the US (mean 17.5%). Ampicillin resistance ranged from 5.7% in Germany to 34.8% in the US (mean 17.6%). Trimethoprim-sulfamethoxazole (TMP/SMX) resistance ranged from 15.2% in the US to 52.9% in Brazil (mean 29.7%). There was little resistance to other drugs. In regard to M. catarrhalis, ß-lactamase production ranged from 79.0% in Germany to 97.5% in Brazil (mean 90.8%). There was little resistance to other drugs. Levofloxacin demonstrated excellent efficacy against all three pathogens, with 100% of M. catarrhalis and H. influenzae susceptible, and 99.6% of S. pneumoniae susceptible.

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Improved Pharmacological Features for Levofloxacin Compared to Ciprofloxacin

In addition to the symposium, numerous additional presentations focused upon levofloxacin, particularly addressing its use for RTIs. One important preclinical study outlined by Dr. Andrea Novelli et al., Università degli Studi, Florence, Italy, reported that the duration of the post-antibiotic effect (PAE) was significantly longer for levofloxacin compared to ciprofloxacin for both S. pneumoniae and M. catarrhalis strains. Levofloxacin also had a long post-antibiotic sub-MIC effect (PA-SME) suprainhibitory dose of 0.25 x MIC with a delay in regrowth of 2-3 hours in comparison to control values for both M. catarrhalis and H. influenzae. In sharp contrast, ciprofloxacin was not able to produce any effect on the H. influenzae strains. These results, coupled with levofloxacin's excellent spectrum of activity and pharmacokinetic properties, show that it would be effective in a once-daily administration schedule for treating RTIs.

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Levofloxacin - Effective against All S. pneumoniae

Two reports by Dr. J.B. Kahn et al., Ortho-McNeil Pharmaceutical, Raritan, NJ, USA, emphasized the usefulness of levofloxacin in RTIs. In the first study, 65 adults from seven studies with CAP were enrolled. Twenty-eight cases with intermediate-level penicillin-resistant S. pneumoniae (PISP) were identified, ten with high-level penicillin-resistant S. pneumoniae (PRSP), ten with PISP plus macrolide-resistant S. pneumoniae (MRSP), four with PRSP and MRSP, and thirteen with MRSP. All patients were successfully treated with levofloxacin 500 mg, PO or IV, once daily, for 7 to 14 days. All S. pneumoniae isolates were eradicated and the clinical success rate was 100% for all groups except the MRSP group which was still very successfully treated in 92% of cases (Table 1). These results demonstrate the effectiveness of levofloxacin in the treatment of CAP due to high-level PRSP and MRSP.

Table 1. Clinical response in patients with community-acquired pneumonia caused by penicillin- and/or macrolide-resistant Streptococcus pneumoniae
Table_1

In their second report, levofloxacin was evaluated in the treatment of PRSP or multiresistant pneumococcal strains (DRSP). Levofloxacin 500 mg IV or PO once daily was given for 7-14 days. One thousand and six patients were entered in the study as of mid-April 1999, taken from 339 study sites. Five hundred and thirteen patients were clinically evaluable, with 211 microbiologically evaluable. Clinical response at post-therapy revealed a cure rate of 81%, improvement rate of 13%, and failure rate of 6%, thus, giving a 94% clinical success rate. Eradication rates ranged from 94-100%, with all penicillin-resistant strains being eradicated.

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Latest Surveillance Data Reported - Safety of Levofloxacin Confirmed

An important post-marketing surveillance (PMS) study reporting on the actual safety of levofloxacin following five years of use in Japan was presented by Daiichi Pharmaceutical Co., Ltd., Japan. This report also analyzed the relations between occurrence of central nervous system (CNS) disorders and concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs). There were two aspects to the survey; a phase IV study in which physicians were requested to record at least three pieces of information on five consecutive patients treated with levofloxacin (patient characteristics, treatment method and ADRs), and secondly, spontaneous reports of ADRs sent to the Drug Safety Administration Department of Daiichi Pharmaceutical Co., Ltd. A total of 260 ADRs were reported in 203 of 16,161 patients, representing an incidence rate of 1.3%, an even lower rate than that of ofloxacin, levofloxacin's very safe parent compound. This rate was also lower than that reported in the phase II-III trial of 2.8%. The distribution of ADRs is shown in Figure 3.

Figure 3. Distribution of abverse drug reactions (ADRs) in phase IV study.
Figure_3
Most frequently reported ADRs of levofloxacin in phase IV study (> 0.05% of incidence rate)
Gastrointestinal : abdominal pain, diarrhea, nausea
Liver : abnomal hepatic function (increased levels of s-GOT or/and GPT)
Skin : rash
CNS : dizziness
a: Adapted from Hanafusa T, et al. Drugs 1993; 45 (Suppl 3) : 441-2, with the permission of Adis International Ltd.

The most frequently reported ADR was GI-related (abdominal pain, diarrhea and nausea). There was a small percentage of liver alterations (increased levels f s-GOT and/or GPT) although no clinical correlation was noted.

The incidence rate of CNS disorders in patients taking both levofloxacin and NSAIDs was 0.1% (6/4,670) and there were no differences compared to those patients not taking NSAIDs (0.1%, 12/11,491). In contrast, spontaneous reports demonstrated that those taking NSAIDs had a higher rate of CNS disorders. However, when further analyzed, there was no statistically significant difference between patients taking concomitant NSAIDs and those who did not. Despite this, it was recommended that patients with preexisting risk factors for conditions such as renal or CNS disorders, should be monitored when taking both levofloxacin and NSAIDs

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