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Highlights from the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy
San Francisco, USA, September 26-29, 1999

CONTENTS

Introduction

Levofloxacin Continues to Maintain Wide Spectrum of Activity

Efflux Pump Inhibitors Potentiate Activity of Levofloxacin

International Surveillance Study Update

Resolution of CAP Symptoms Occurs Faster with Levofloxacin

Significant Cost Savings Associated With Levofloxacin Use in CAP

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Introduction

Picture_1The 39th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) remains one of the major infectious disease meeting worldwide. Recently held in San Francisco, it provided an exceptional forum in which the latest developments and trends could be presented and discussed. This publication reports on some of the highlights revealed at this meeting, with particular reference to the problem of resistance among respiratory tract pathogens, and the role of levofloxacin in combating this worrisome trend.

Picture_2Levofloxacin, a new respiratory fluoroquinolone, possesses strong activity against both penicillin- and multidrug-resistant organisms. It also has exceptional bioavailability, a wide spectrum of activity, and from post-marketing studies has been demonstrated to be extremely well tolerated. This latter feature has become of great importance as some of the other newer fluoroquinolones are now no longer recommended due to unacceptable side effects, none of which are associated with levofloxacin. Thus, physicians and researchers alike have realized the many benefits provided by levofloxacin, with these excellent features confirmed in many in vitro as well as clinical studies.

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Levofloxacin Continues to Maintain Wide Spectrum of Activity

A number of studies presented data showing that levofloxacin has maintained its excellent antibacterial activity, with this is being widened to include anti-anaerobic uses. A paper reported by Dr. H. Grimm et al., from the German Multicentre Study Group, Weingarten, Germany, evaluated the susceptibility of 3,055 unselected freshly-isolated respiratory tract pathogens (401 Streptococcus pneumoniae, 389 Staphylococcus aureus, 410 Haemophilus influenzae, 366 Moraxella catarrhalis, 373 Escherichia coli, 360 Klebsiella pneumoniae, 372 Enterobacter spp., and 384 Pseudomonas aeruginosa). The minimum inhibitory concentrations (MICs) of levofloxacin were compared with those of ciprofloxacin, amoxicillin-clavulanic acid, cefuroxime axetil and clarithromycin (Table 1).

Table 1. In vivo activity of levofloxacin and four other antibiotics against respiratory tract pathogens showing MIC90/percent resistance
Table_1

Levofloxacin had the highest activity against Enterobacteriaceae, H. influenzae and M. catarrhalis. It was also very effective against S. pneumoniae strains which were resistant to ciprofloxacin. In contrast, none of the isolates were resistant to levofloxacin.

In addition to these results, levofloxacin was also shown to have anti-anaerobic activity when combined with clindamycin or metronidazole. Dr. K.L. Credito et al., Hershey Medical Center, Hershey, PA, USA, evaluated 12 anaerobic strains from recent clinical isolates and found that the MICs of antibiotics alone were 0.5-8.0 µm/ml for levofloxacin, 0.008-2.0 µm/ml for clindamycin, and 0.25->16 µm/ml for metronidazole. However, when combined, synergy was found between levofloxacin and metronidazole in the two strains of Bacteroides fragilis used in the study, and between levofloxacin and clindamycin in one strain. Such synergistic activity allows levofloxacin to widen its clinical applications, with expected efficacy in treating mixed aerobic and anaerobic infections.

A Spanish study reported by Dr. J. Garcia-Rodriguez et al., Department of Microbiology, University Hospital, Salamanca, Spain, looked at the growing problem of ß-lactamase-negative, ampicillin-resistant strains of H. influenzae. These strains are also resistant to many other antibiotics, including amoxicillin-clavulanic acid, cefuroxime axetil and loracarbef. Dr. Garcia-Rodriguez found that levofloxacin maintained its activity against both ampicillin-sensitive and ampicillin-resistant H. influenzae strains, including those resistant to other macrolides and ß-lactams (Figure 1).

Figure 1. In vivo activity (mg/l) of ß-lactams, macrolides and newer fluoroquinolones against ampicillin resistant, ß-lactamase negative Haemophilus influenzae.
Figure_1

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Efflux Pump Inhibitors Potentiate Activity of Levofloxacin

The role of efflux pumps in the development of resistance has become more widely understood, and with this knowledge has come the opportunity to develop new ways to counteract this resistance mechanism. Two of the most innovative and cutting edge papers dealing with this subject were reported by Dr. T.E. Renau and Dr. D. Griffith, Microcide Pharmaceuticals Inc., Mountain View, CA, USA. These researchers developed a potentiator that inhibits the efflux pump action, thereby enhancing the activity of fluoroquinolones against P. aeruginosa. In the preliminary study, a broad spectrum efflux pump inhibitor (EPI) in P. aeruginosa was identified as MC 207,110 which had minimal antibacterial activity itself, but potentiated the activity of levofloxacin eight-fold at 10 µg/ml.

To investigate clinical applications of this EPI, a study was performed in an animal model. Mice were treated with levofloxacin 30 mg/kg every four hours alone or in combination with different doses and dosing intervals of the EPI. Results revealed that as the frequency of EPI dosing increased, the potentiation effects also became more rapid (Table 2).

Table 2. Neutropenic mouse thigh model showing potentiation of levofloxacin by efflux pump inhibitor
Table_2

Thus, by inhibiting the efflux pumps, the activity of levofloxacin against P. aeruginosa both in vitro and in vivo was potentiated. Certainly in this time of increasing concern over resistance, this appears to be an important breakthrough in maintaining antibacterial efficacy.

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International Surveillance Study Update

The ongoing increase in resistance, particularly among S. pneumoniae, has led to the latest community-acquired pneumonia (CAP) guidelines from the Infectious Disease Society of America (IDSA) recommending empiric fluoroquinolones such as levofloxacin for these infections. To update the reader on the latest resistance statistics, the following provides a brief overview of some of the major surveillance studies.

The Alexander project was reported by Dr. D. Felmingham et al., GR Micro Ltd., London, UK, from The Alexander Project Group. They reported that of 8,885 community-acquired respiratory isolates, 95% of the 4,014 S. pneumoniae isolates were susceptible to ofloxacin, 77.7% to ceftriaxone, 76.5% to amoxicillin-clavulanic acid, 74.5% to doxycycline, 71.9% to cefuroxime axetil, 71.8% to erythromycin, 64.8% to penicillin, and 62.3% to trimethoprim-sulfamethoxazole. ß-lactamase production was seen in 20.2% of H. influenzae and 93.6% of M. catarrhalis isolates. Regardless of species, ofloxacin, chloramphenicol and amoxicillin-clavulanic acid were the most active of the orally bioavailable compounds.

The SENTRY Antimicrobial Surveillance Program was reported by Dr. H.S. Sader et al., São Paulo University, São Paulo, Brazil. This was a surveillance report of resistance in Latin America from 1997 to 1998, and authors found that only 60.9% of 553 S. pneumoniae were susceptible to penicillin, 28.7% were intermediate-resistant strains, and 10.4% had high-level resistance. The only agents that inhibited 100% of S. pneumoniae isolates were new fluoroquinolones and vancomycin. In general, ß-lactams were less active against penicillin-resistant S. pneumoniae (PRSP). Production of ß-lactamase was seen in 91.2% of M. catarrhalis and 12.6% of H. influenzae. These combined results provide a snapshot view of resistance trends - a view which confirms the urgent need for effective agents such as levofloxacin, and the need for advocating its judicious use in order to maintain its exceptional activity.

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Resolution of CAP Symptoms Occurs Faster with Levofloxacin

Many of the presentations regarding the fluoroquinolones looked at their role in managing respiratory tract infections (RTIs), particularly CAP. A Community-Acquired Pneumonia Intervention Trial assessing levofloxacin, and reported by Dr. T.J. Marrie et al., Queen Elizabeth II Health Sciences Centre, Halifax, Canada, randomized hospitals to use either a critical pathway with levofloxacin (500 mg once daily) or standard therapy.

Following treatment, features which were associated with patients completely free of CAP symptoms at six weeks were: younger age, lower pneumonia severity index (PSI) scores, lower blood pressure, lower respiratory rate and less likely to be asthmatic or have chronic obstructive pulmonary disease (COPD). Symptom-free patients were also more likely to have undergone treatment at hospitals that had used the levofloxacin critical pathway model rather than conventional treatment. Those treated with a ß-lactam were more likely to have symptoms for a longer duration. Using a multivariate model to assess these factors, it was then shown that treatment with levofloxacin was the most significant predictor of symptom resolution (risk ratio = 1.7, p = 0.10, Table 3).

Table 3. Predictors of community-acquired pneumonia related symptom resolution at six weeks post-therapy : Multivariate logistic regression model
Table_3

Thus, treatment with levofloxacin was clearly better at reducing CAP symptomatology when compared with other agents. Levofloxacin also had a much greater safety profile than other agents, including newer macrolides such as azithromycin and clarithromycin. These results confirm the efficacy and usefulness of levofloxacin in managing patients with CAP, both in the outpatient and hospital setting.

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Significant Cost Savings Associated With Levofloxacin Use in CAP

Considering the importance of cost savings in health systems around the world, an extremely timely and thought-provoking paper was presented by Dr. C. Palmer, MEDTAP International, Bethesda, MD, USA, and colleagues from Canada and the UK. This study evaluated the use of a critical pathway designed to manage CAP more efficiently than conventional therapy. It was hypothesized that the critical pathway would result in reduced costs due to less low-risk patients being admitted to hospital, a reduced use of intravenous administration, decreased stay in hospital, less patients requiring multiple treatment schedules and an outcome equal or better than conventional treatment. Nine participating Canadian hospitals were randomized to use the critical pathway (716 patients) and ten used conventional therapy (1,027 patients).

A statistically greater number of levofloxacin patients were initially treated as outpatients compared to conventional therapy (54% vs 38%; p = 0.01). The average stay for those admitted to hospital treated and with levofloxacin was 1.6 days less than conventional therapy, and costs of inpatient antibiotics were less for levofloxacin (mean $124) compared to the conventional arm (mean $171). This resulted in substantial cost savings per patient using the critical pathway (Table 4).

Table 4. Pneumonia-related summary costs, 1998 $CDN
Table_4

While proving itself to be significantly cheaper, levofloxacin usage also achieved excellent clinical results, with no significant differences found between patients treated with levofloxacin or conventional therapy.

Taken together, these wide-ranging preclinical, clinical and cost-effectiveness studies confirm the important role levofloxacin is carving out for itself, and show the way forward for effective treatment of RTIs.

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Last updated December 13, 1999.