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Reports from the 6th International Symposium on New Quinolones
Denver, USA, November 15-17, 1998

CONTENTS

INTRODUCTION

SUPERIOR PHARAMACOLOGIC FEATURES ASSOCIATED WITH LEVOFLOXACIN

CLINICAL EFFICACY OF LEVOFLOXACIN IN RTIs CONFIRMED

LEVOFLOXACIN COST-EFFECTIVE IN A CRITICAL PATHWAY MEDEL FOR CAP

SINUSITIS - LEVOFLOXACIN AS EFFECTIVE AS MACROLIDES




INTRODUCTION

The 6th International Symposium on New Quinolones, recently held in Denver, Colorado, USA, from November 15-17, 1998, highlighted the most up-to-date research data available on this exceptionally useful class of drugs. One of the most important changes since the last congress has been in the recognition that newer fluoroquinolones, such as levofloxacin, are an extremely useful therapeutic option for the management of lower respiratory tract infections (LRTIs). The greater antibacterial spectrum of these agents has resulted in the Infectious Diseases Society of America listing the newer fluoroquinolones as among the generally preferred antimicrobials for managing community-acquired pneumonia (CAP) in both outpatient and hospitalized patients. At the forefront of this move toward effective LRTI treatment is levofloxacin, a broad-spectrum fluoroquinolone with excellent in vitro activity against the common respiratory tract pathogens, including the atypical pathogens such as Mycoplasma, Chlamydia and Legionella species. This report highlights some of the most important findings to emerge from this meeting, with particular reference to levofloxacin.


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SUPERIOR PHARAMACOLOGIC FEATURES ASSOCIATED WITH LEVOFLOXACIN

Levofloxacin possesses not only an excellent antibacterial spectrum against RTI pathogens, but also demonstrates significant pharmacokinetic and pharmacodynamic features which provide it with advantages over other commonly used agents. Results from an open-label, randomized trial was presented by Dr. James B. Kahn et al. Ortho-McNeil Pharmaceutical, Raritan, NJ, USA. They demonstrated that levofloxacin 500 mg or 750 mg once daily achieves higher steady-state concentration in plasma, epithelial lining fluid (ELF) and alveolar macrophages (AM) than ciprofloxacin 500 mg twice daily (Figure 1).

Figure 1. Levofloxacin steady-state concentration in AM at each samplinge time compared with ciprofloxacin

Figure 1

Fig 1 table

In addition, levofloxacin maintained concentrations well above the minimum inhibitory concentrations (MICs) for common respiratory tract pathogens after 24 hr. Adding to this data was a report from Dr. B. Wiedemann and Dr. E. Pfeil, University of Bonn, Bonn, Germany, outlining results from their in vitro dilution model which measured the activity of levofloxacin against Streptococcus pneumoniae, Streptococcus pyogenes, Haemophilus influenzae, Mollaxella catarrhalis and Klebsiella pneumoniae and compared it to those obtained for 500 mg ciprofloxacin. Even after a single dose of levofloxacin, the viable cell counts of all pathogens were steadily reduced two to five times within 24 hr and the long half-life ensured that bacterial regrowth did not occur during the experiment. In contrast the kill kinetics with ciprofloxacin 500 mg showed that counts of S. pneumoniae and S. pyogenes increased to pretherapy levels after 5 hr and 11 hr, respectively. The area above the kill curve (AAC) values at 12 hr reveals the high pharmacodynamic activity of levofloxacin compared to ciprofloxacin (Figure 2) and this trend becomes even more obvious for the 24 hr period.

Figure 2. Area above killcurve (AAC) for 12 hours

Figure 2

These results are of particular significance, because it has become increasingly apparent that MIC alone is not a sufficient indicator of an agent's activity and pharmacodynamic parameters are required to gain a real picture of an antibacterial agent's action in vivo. When taking such a wider, more realistic view, levofloxacin is shown to possess important pharmacologic advantages over its competitors, which allow it to be administered extremely effectively in a once-daily administration schedule.

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CLINICAL EFFICACY OF LEVOFLOXACIN IN RTIs CONFIRMED

A large number of studies confirmed that levofloxacin possesses excellent efficacy in a range of RTIs. An analysis of seven clinical trials was carried out by Dr. B.A. Wiesinger et al. Ortho-McNeil Pharmaceutical, USA to evaluate the efficacy of levofloxacin for the treatment of adults with community-acquired pneumonia (CAP) due to high level penicillin-resistant (penicillin MIC > 2 µg/ml) pneumococci and pneumococcal strains of intermediate susceptibility (penicillin MIC 0.125-1 µg/ml). Patients received 500 mg levofloxacin daily for 7-14 days. Levofloxacin achieved a 100% clinical success rate for both penicillin-resistant and penicillin-intermediate strains at the post-therapy assessment (Table 1).

Table 1. Clinical response at approximately 2-7 days posttherapy
Table_1

Susceptibility to levofloxacin was shown to be independent of penicillin-resistance, a very useful feature in an era of increasing multidrug resistance.
Another clinical trial looked at the efficacy of levofloxacin in the treatment of CAP due to Legionella species. The results of this study reported by Dr. R.R. Williams et al. The R.W. Johonson Pharmaceutical Research Institute, Raritan, NJ, USA, provided further evidence for the importance of levofloxacin in the management of this disease. A non-randomized, open-label study was performed in which patients received 500 mg levofloxacin once daily for 7-14 days. Levofloxacin achieved an excellent 92% clinical success rate, (73% cure, 19% improvement) and there were no cases of relapse or death. Safety evaluation reported a 38% adverse drug reaction (ADR) rate, 35% being mild-moderate. Only 3% were probably/definitely attributable to levofloxacin and these results compare very favourably to that achieved by other agents used for treating these infections leading to the conclusion that levofloxacin is an effective treatment of Legionella CAP.
Recently the Infectious Diseases Society of America guidelines for CAP have listed the newer fluoroquinolones in the preferred antimicrobial category for managing Mycoplasma pneumoniae and Chlamydia pneumoniae CAP. To confirm the utility of levofloxacin in this setting, the same research group performed a non-randomized open label study of 655 CAP patients, 20% of whom had atypical pathogens identified as their causative etiology (15% M. pneumoniae and 5% C. pneumoniae). Patients were treated with 500 mg levofloxacin for 7-14 days. At the post-therapy analysis (5-7 days following the end of therapy) levofloxacin achieved an 96.4% clinical success rate for treating C. pneumoniae (53.6% cured, 42.9% improved). Only 3.6% were judged to have failed therapy. Levofloxacin was even more effective in managing M. pneumoniae with a clinical success rate of 98% (71.1% cured, 26.9% improved) and only one failure. There were no relapses in the Chlamydia group and a low rate of 2.2% for Mycoplasma confirming that not only was levofloxacin very effective in treating infections due to these atypical pathogens, but was also associated with a low risk of relapse. This is a particularly important feature in view of the fact that infections with C. pneumoniae tend to recur, often requiring repeated courses of antibiotics.


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LEVOFLOXACIN COST-EFFECTIVE IN A CRITICAL PATHWAY MEDEL FOR CAP

An algorithm which would provide the physician with a more cost-effective management of CAP was assessed in a randomised trial by Dr. T. Marrie et al. for the Capital Study Investigators and Janssen-Ortho Inc., Canada. In an effort to reduce length of stay, and use of medical care resources, the authors evaluated a critical pathway model which utilised levofloxacin for the management of CAP, compared to physicians usual treatment. The critical pathway is outlined in Figure 3.

Figure 3. Critical pathway for the management of CAP

Figure 3

Data from patients presenting to 19 hospitals (10 critical care pathway, 10 conventional treatment) was collected during the period January 1- July 31, 1998. A pneumonia specific severity of illness scoring system (PSSI) was developed in which patients were assigned a score based upon a range of demographic factors, comorbidity, physical examination findings and laboratory findings (Table 2).

Table 2. Pneumonia-specific severity-of-illness scoring system (PSSI)
Table_2

a Neoplastic disease is defined as any cancer except basal-or squamous-cell cancer of the skin active at the time or presentation or diagnosed within one year of presentation.
b Liver disease is defined as a clinical or histologic diagnosis or cirrhosis or another form of chronic liver disease, such as chronic active hepatitis.
c Congestive heart failure is defined as systolic or diastolic ventricular dysfunction documented by history, physical examination, chest radiograph,echocardiogram, multiple gated acquisition scan or left ventriculogram.
d Cerebrovascular disease is defined as a clinical diagnosis of stroke or transient ischemic attack or stroke documented by magnetic resonance imaging or computed tomography.
e Renal disease is defined as a history of chronic renal disease or abnormal blood urea nitrogen and creatinine concentrations documented in the medical record.
f Altered mental status is defined as disorientation with respect to person, place or time that is not known to be chronic, stupor or coma.
g Oxygen saturation < 90% on pulse oximetry or intubation before admission is also considered abnormal.
Adapted from Fine MJ et al. N Engl J Med 1997; 336: 243-50.

Patients in the critical pathway and conventional groups had similar disease severity at baseline. By using the critical pathway the admission rate for low-risk patients (PSSI class I-III) was decreased from 50% to 30%, confirming the validity of the PSSI as a useful adjunct to clinical judgment. Despite greater disease severity, patients who were treated at critical pathway sites, which used levofloxacin as the antibiotic of choice, required fewer days of intravenous therapy and were more likely to receive antibiotic monotherapy. Institutions which utilised the pathway had an overall absolute reduction of 10% in the rate of admission and a one day decrease in length of stay, resulting in a saving of 1.5 bed-days per patient managed. Researchers commented that the use of the PSSI score and levofloxacin treatment were the most effective components of the critical pathway and that significant cost savings are possible by using this agent in this manner.


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SINUSITIS - LEVOFLOXACIN AS EFFECTIVE AS MACROLIDES

Not only has levofloxacin been shown to be an excellent agent for the treatment of LRTI, but not surprisingly, it has also demonstrated great efficacy in the treatment of upper RTI (URTIs) such as sinusitis. Results form a multicenter, double-blind study comparing the safety and clinical efficacy of levofloxacin versus clarithromycin in this setting were reported by Dr. B. Lasko et al. of the Canadian Collaborative Sinusitis Study Group and Janssen-Ortho Inc., Toronto, Ontario, Canada. A total of 236 patients aged over 18 years with acute sinusitis were randomized and 235 received at least one dose of study drug (118 levofloxacin 500 mg once daily, and 117 clarithromycin 500 mg twice a day, both given for 10-14 days). The clinical success rate in the 98 levofloxacin evaluated patients was 93.9% (40.8% cured + 53.1% improved). The results for clarithromycin were 29% cured and 64.5% improved giving a clinical success rate of 93.5%. Not only was once daily levofloxacin shown to be as effective as clarithromycin twice daily, but it was also better tolerated by the patients. Of significance was the fact that a higher proportion of levofloxacin treated patients were cured with complete absence of signs or symptoms compared to clarithromycin and that it was associated with a faster clinical improvement.

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