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toumei ../image Congress Report

The 7th International Symposium on New Quinolones
June 10-12, 2001 Edinburgh, Scotland

CONTENTS

Introduction

The Science of the Fluoroquinolones: How It Relates to the Clinical Practice

Extensive Use of Levofloxacin Not Associated with Increased Resistance

Selection of Fluoroquinolone-resistant Mutants

Pharmacokinetic and Pharmacodynamic Data: Tools for Developing Effective Dosing Schedules

An Expanding Role for the Fluoroquinolones

Levofloxacin-proven Efficacy in Seriously Ill CAP Patients

Levofloxacin has Lowest MIC Against Legionella Pnemophila Compared to Other Agents Tested

L. Pneumophila Effictively Managed by Levofloxacin

C. Pneumoniae Emerging as Frequent Cause of Community-accquired RTI

Reduced Risk of Infection Usind Levofloxacin for Prophylaxis

New Therapy for Anaerobic Infections

High Dose Levofloxacin Therapy Safe and Effective in Complicated Skin Infections

Clarifying the Issure of Fluoroquinolone Penetration Into Cerebrospinal Fluid

Safety Update - How the Fluoroquinolones Differ


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Introduction

Quinolones have undergone significant evolution since nalidixic acid was first introduced in 1960. The addition of the fluorine atom to the quinolone nucleus, producing the fluoroquinolones, was a major leap forward in the early 1980s. In the last decade, there has been a further advance with the development of the 'respiratory fluoroquinolones'. These latter agents possess an expanded spectrum of activity and better pharmacological features. The significant improvement in formulations has led to an explosion of these agents in the therapeutic strategies used by many physicians. Thus, the International Symposium on New Quinolones has increased in size and importance, as it is the only meeting to focus solely upon these extremely useful agents. The 7th Meeting in this series, which was recently held in Edinburgh, Scotland from June10-12, 2001, provided an unparalleled opportunity for researchers and clinicians alike to learn about all of the ongoing advances occurring in relation to this class of antimicrobials.
A wide ranging scientific program provided in depth data on important issues covering in-vitro activity, clinical trial results and the issue of adverse events. This latter problem has sparked increased interest with the recognition that some of the new agents possess unacceptable adverse event profiles, particularly with regard to liver, central nervous system and cardiovascular toxicity. One agent that has been proven to be very safe is levofloxacin, and there were a large number of presentations focusing upon this agent, which possesses both excellent activity but also an unequalled safety profile. The following review outlines a selection of the most important and thought-provoking presentations at the meeting, which cover some of these contentious issues.



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toumei ../image The Science of the Fluoroquinolones: How it Relates to the Clinical Practice

One of the major symposia held during the course of the meeting was co-chaired by Dr. George L. Drusano, Professor and Director of the Division of Clinical Pharmacology, Albany Medical College, Albany, NY, USA and Dr. Robert Siegel, Clinical Associate Professor of Medicine, The Mount Sinai School of Medicine, New York, NY, USA, who noted that resistance to fluoroquinolones has remained relatively low, and stressed the need to maintain this favorable situation. One way forward that allows for high efficacy, a low rate of side effects, and prevention of resistance is to utilize knowledge about structure-activity relationships. This information, coupled with clinical trial results, highlights how basic scientific data can be used to improve treatment outcome.
   In the first part of this symposium, Dr. Karen Bush, Senior Research Fellow, The Robert Wood Johnson Pharmaceutical Research Institute, Raritan, NJ, USA reported a comprehensive overview of basic fluoroquinolone data. She noted that investigation into underlying resistance mechanisms is useful in outlining how they should be used to avoid undue selection pressure on developing resistant organisms.


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toumei ../image Extensive Use of Levofloxacin Not Associated with Increased Resistance

While levofloxacin has been used extensively over the past few years, surveillance data has shown that over the period 1994-98, susceptibility of Streptococcus pneumoniae to levofloxacin has been maintained at 99.6%. This is confirmed by US results from the ongoing TRUST (Tracking Resistance in the United States Today) study, which have demonstrated a 0.6% resistance rate to levofloxacin in 1996-97, dropping to 0.1% in 1997-98, and then maintained at 0.6% for the past two-year period.
   Fluoroquinolone resistance most frequently develops following mutations in the parC and gyrA quinolone-resistance-determining regions (QRDR). However, non-QRDR target mutations have also been recorded, including a parC mutation in Staphylococcus aureus and a parE mutation in pneumoniae. Another method behind the development of fluoroquinolone resistance is that of efflux pumps. These pumps operate in both Gram-positive and Gram-negative bacteria illustrated by the acrA pump in Escherichia coli, which is regulated by mar (multiple antibiotic resistance) or sox (superoxide resistance) regulons. Plasmid-mediated resistance is another mechanism reported to cause fluoroquinolone resistance in Gram-negative bacteria.
   Dr. Bush then discussed the mutations leading to fluoroquinolone resistance in more detail. Research has shown that a single mutation in gyrA is associated with increased MICs to sparfloxacin and gatifloxacin. In contrast, this mutation is not associated with increased MICs to levofloxacin, ciprofloxacin, or trovafloxacin. It has been shown that in order to develop levofloxacin resistance, two mutations are required, one in the gyrase and another effecting the topoisomerase. This has been confirmed in an evaluation of 25 fluoroquinolone-resistant isolates, in which all had gyrA mutations, 24 had parC mutations and 15 had parE mutations. For full resistance to develop, it was necessary to have at least two mutations. This gives levofloxacin a practical advantage over some of the other fluoroquinolones, as the need for two mutations to occur means that levofloxacin is markedly less likely to be associated with the development of resistance.



toumei ../image Selection of Fluoroquinolone-resistant Mutants

Levofloxacin has been shown in studies to be the fluoroquinolone least frequently associated with the selection of quinolone-resistant S. pneumoniae. Investigation using different multiples of MIC has confirmed that the quinolone most often selected for developing resistance was sparfloxacin, followed in descending order by trovafloxacin and ciprofloxacin, then less often by levofloxacin and gatifloxacin. Other studies using hollow fiber techniques simulating human pharmacokinetic parameters to look at S. pneumoniae isolates have shown that while initial MICs for ciprofloxacin ranged from 1-4µg/ml at 24hr and 48 hr, there was an increase in the MIC for all strains. In contrast, there was no growth with levofloxacin at 24 and 48 hrs, and those that did have growth had no increase in MIC from the initial value (Table 1). This highlights that under the same conditions, levofloxacin does not select for resistant mutants, while ciprofloxacin does.


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Table 1. No in-vitro selection of levofloxacin–resistant Streptococcus pneumoniae at low peak/MIC and AUC/MIC ratios
Table 1
Abbreviations: NG = no growth, AUC = area under the plasma concentration-time curve, MIC = minimum inhibitory concentration.
Adapted from Lacey MK, et al. Antimicrob Agents Chemother 1999; 43: 672–7.
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toumei ../image Pharmacokinetic and Pharmacodynamic Data: Tools for Developing Effective Dosing Schedules

Dr. George L. Drusano provided a clear summary of how pharmacokinetic and pharmacodynamic data can be used to develop the best dosing strategies, as well as to predict clinical outcome. Using pharmacodynamic data from a mouse thigh infection model, Dr. Drusano emphasized that even after 6 months of following pathogenic isolates, researchers had been unable to develop levofloxacin-resistant S. pneumoniae mutants. In contrast, a major inoculum effect was seen for Pseudomonas aeruginosa isolates, which is due to the resistant mutant subpopulation already present. As P. aeruginosa can have a resistant and susceptible population already present, the question arises as to whether it is possible to identify an exposure that will stop the resistant population from taking over the whole population. Investigations into this have demonstrated that an AUC/MIC ratio of 157 prevents growth of resistant P. aeruginosa mutants following levofloxacin therapy.
   Turning to S. pneumoniae, a model was developed to identify a dose that would suppress the development of resistant mutants. Evaluation of levofloxacin and the pneumococcus revealed that no pneumococcal resistant mutants could be recovered in the mouse thigh model. However, this was not the case with ciprofloxacin, which selected resistant mutants on 2 times MIC ciprofloxacin plates. Further investigation using reserpine, which acts as a pump inhibitor, showed that the ciprofloxacin-resistant isolate was a pump mutant. Identification of the exposure required to kill the pump mutants in addition to wild type isolates, along with drug clearance and distribution, as well as pathogen MICs, allows the dose of drug required to achieve a specific microbiological endpoint to be calculated. Using this methodology, it was shown that using a 500 mg once daily dose of levofloxacin, 98% of the time an AUC/MIC ratio of 27 would be achieved, and 95% of the time a one log drop using an AUC/MIC ratio of 34.5 would be reached. This was then used in the clinical setting, with 136 patients evaluated, 20 of whom had pneumococcal pneumonia. The mean peak/MIC ratio was 13.4 (range = 4.2-26.7) and mean AUC/MIC ratio was 112.8 (range = 25.7-248.8). All patients achieved microbiological eradication. Dosing regimen studies using levofloxacin, ciprofloxacin, and ampicillin revealed that levofloxacin administration was not associated with the emergence of resistance and no change in MICs. This was in sharp contrast to ciprofloxacin, which was associated with regrowth of pneumococcal isolates within 48 hrs of treatment (Figure 1). The results led Dr. Drusano to conclude that optimal peak/MIC and AUC/MIC values vary according to the pathogen. With regard to fluoroquinolone treatment of S. pneumoniae, an AUC/MIC ratio of either 100 or 125 gives a negative predictive value of 0 and a positive predictive value with worse odds than a coin toss. Experimental data in-vitro, in animal models, and in the clinic supports a free drug AUC/MIC ratio of 25-35 as the breakpoint in pneumococcal pneumonia and data indicate that emergence of resistance is very unlikely when any newer fluoroquinolone is used.


  Figure 1. Comparative bacterial activity for ampicillin, ciprofloxacin, and levofloxacin.
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Abbreviation: CFU = colony forming unit.
Adapted from Lacey MK, et al. Antimicrob Agents Chemother 1999; 43: 672–7.

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An Expanding Role for the Fluoroquinolones

The clinical implications of this research were then reviewed by Dr. Thomas M. File, Jr., Professor of Internal Medicine, Northeastern Ohio Universities College of Medicine, Rootstown, and the Chief of Infectious Disease Service, Summa Health System, Akron, OH, USA. The newest agents among the fluoroquinolones, including levofloxacin, possess excellent bactericidal activity against key respiratory tract infection (RTI) pathogens. This includes S. pneumoniae as well as drug-resistant S. pmeumoniae (DRSP) isolates, Haemophilus influenzae, Moraxella catarrhalis, atypicals (Mycoplasma spp., Chlamydia spp., Legionella spp.), methicillin-sensitive S. aureus and Enterobacteriaceae.
   The incidence of penicillin resistance among S. pneumoniae (PRSP) is increasing worldwide, and the clinical significance of this is now well documented in a range of infections, including RTIs. This problem is compounded by the fact that penicillin-resistant S. pneumoniae are often multidrug resistant. Clinicians and patients alike are extremely fortunate that these pathogens remain exquisitely sensitive to levofloxacin and other fluoroquinolones. Such in-vitro activity has been supported by clinical studies, leading to the recommendation of respiratory fluoroquinolones such as levofloxacin prominently in all guidelines worldwide.
   A huge database has been built up for levofloxacin - far greater than for any of the other fluoroquinolones, and in fact larger than most other antibiotics. Levofloxacin has been available in Japan since 1993, and in the USA since 1997. It has been used extensively during this time, with more than 200 million prescriptions now documented. Despite this huge use, there are no signs of any significant resistance to this agent developing. The database provides irrefutable evidence for the efficacy and safety of levofloxacin in actual clinical use. This is true in all patient subgroups, including the elderly as well as those with reduced renal or other organ function, and in real situations where patients are often taking a range of other medications. In all situations, levofloxacin has proven itself to be an extremely beneficial agent. A number of randomized trials strongly support the utility of levofloxacin in the clinical setting and its equal or superior efficacy in comparison with comparator agents such as ceftriaxone and cefuroxime axetil or amoxicillin-clavulanic acid or ceftriaxone. Some of these trials have shown a significant benefit for levofloxacin. Major results from one study revealed the percentage response in severe community-acquired pneumonia (CAP) to be 96% for levofloxacin compared to 90% for ceftriaxone/cefuroxime axetil plus erythromycin (95% CI = -10.7, -1.3). Mortality among hospitalized patients was 1.4% for levofloxacin compared to 5.6% for the comparator, while adverse events were 5.8% in levofloxacin (1.7% nausea and vomiting, 1.4% diarrhea) compared to 8.5% for the comparator (3.0% nausea/vomiting and 3.8% diarrhea).
   A different trial comparing levofloxacin versus azithromycin plus ceftriaxone revealed a clinical response of 95% for levofloxacin versus 91.8% for the comparator. A large non-comparative study with 1,095 patients, including those with DRSP infection, produced a clinical response rate of 94%. Supporting results from other trials, this again demonstrated a very low adverse drug rate. Finally, a trial investigating patients with severe CAP (at least 15% requiring ventilatory support) resulted in a clinical response of 89% for levofloxacin, compared to 83% for those patients treated with ceftriaxone plus erythromycin. This clinical efficacy is further strengthened by economic data confirming levofloxacin to be a more cost-effective regimen. A recent Canadian report assessed 1,700 patients randomized to a clinical pathway utilizing levofloxacin versus standard care. Results at six weeks showed levofloxacin to be independently associated with a greater percentage of symptom resolution. Dr. File concluded that these results taken together undoubtedly support a starring role for levofloxacin in the management of RTI.



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Levofloxacin-proven Efficacy in Seriously Ill CAP Patients

Not only is levofloxacin effective in general RTI, including CAP, but the latest results also show that it is extremely beneficial in treating patients who are seriously ill. A study presented by Dr. James B. Kahn et al., Ortho-McNeil Pharmaceutical, Inc., Raritan, NJ, USA, selected patients with a high risk of mortality (defined as belonging to the Fine IV subgroup of CAP patients). A total of 132 patients received levofloxacin 500 mg IV once daily for one or more days, followed by PO levofloxacin at the same dose for a total of 7-14 days. A randomized comparator group of 137 subjects received ceftriaxone sodium 1-2 g IV or IM every 24 hrs plus erythromycin 500-1000 mg IV every 6 hrs, followed by amoxicillin-clavulanic acid 875 mg PO b.i.d., plus clarithromycin 500mg PO b.i.d. for a total of 7-14 days. Clinical and microbiological responses were assessed. The clinical success rate associated with levofloxacin treatment was 89.5% compared to 83.1% for the other arm of the trial (Table 2). Safety assessment revealed levofloxacin to be well tolerated, with a much lower rate of discontinuations (2.3%) compared to the ceftriaxone/erythromycin arm, followed by the amoxicillin-clavulanic acid/clarithromycin group (8.8%). These results clearly show levofloxacin monotherapy to be effective for treating seriously ill patients with CAP.


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Table 2. Clinical and microbiological response at post–therapy
Table 2
a In the levofloxacin and comparator arms, 40 and 24 patients, respectively, were evaluable for clinical efficacy but not for microbiological efficacy.
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Levofloxacin has Lowest MIC Against Legionella Pneumophila Compared to Other Agents Tested

Atypical respiratory pathogens, L. pneumophila, Mycoplasma pneumoniae and Chlamydia pneumoniae, are becoming increasingly recognized as being important agents causing RTI, with up to 35% of CAP cases attributed to these pathogens. However, it is unusual for these agents to be identified, making it difficult to assess their true prevalence. It is now realized that empiric treatment of CAP should not only cover the common bacterial pathogens (S. pneumoniae, H. influenzae and M. catarrhalis), but should also provide coverage against the atypicals. A study reported by Dr. Mark E. Jones, Associate Director, Focus Technologies, Inc., Hilversum, The Netherlands, and colleagues determined the activity of levofloxacin, erythromycin, azithromycin, clarithromycin and doxycycline against atypical pathogens. This was an international study with isolates from the USA, Finland, Denmark, France, The Netherlands, Scotland, Germany, UK, Spain, Canada and Kenya. Most isolates were respiratory, collected from 1990-1999. Comparison of activity was made using MIC distributions, modal MIC and MIC90. Results confirmed that levofloxacin had the lowest MIC90 (0.03µg/ml) and modal MIC (0.015µg/ml) against L. pneumophila compared to the other antimicrobials tested (Table 3). Levofloxacin and doxycycline had similar activity against M. pneumoniae. Narrow MIC ranges were documented for C. pneumoniae against all agents. Researchers stressed the importance of the finding that for each species tested, levofloxacin MICs fell within a narrow range of values and was not influenced by the reduced macrolide susceptibility seen in two isolates. This macrolide resistance was a cause of concern and indicates the need for ongoing surveillance studies aimed at following the susceptibility of atypical pathogens.


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Table 3. Antimicrobial susceptibilities of 146 isolates of Legionella pneumophila
Table 3
Abbreviation: MIC50, MIC90 = minimum inhibitory at which 50% and 90% of tested strains are inhibited, respectively.
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L. Pneumophila Effectively Managed by Levofloxacin

To add clinical relevance to the in-vitro findings of levofloxacin activity against the atypicals, two separate studies investigating the efficacy of levofloxacin in treating CAP caused by L. pneumophila were reported. The first study, performed by Professor Christian Chidiac, Service des Maladies Infectieuses et Tropicales, Lyon, France was a retrospective analysis of hospitalized patients with CAP, included in an international multicenter prospective randomized study comparing levofloxacin 500 mg once daily versus ceftriaxone 1 g once daily. Patients were enrolled if they presented with the following: clinical signs and symptoms of CAP, with radiological findings consistent with this, CAP was related to L. pneumophila with positive serology (using indirect fluorescent antibody determinations); a single highly increased titre, 1:256 or greater in a patient with an illness compatible with Legionnaires' disease or a four-fold increase in titre. Patients were evaluated at enrollment, during treatment, at the end of the study (2-5 days post-treatment) and at follow-up 14-21 days after therapy. Thirteen patients were identified, all of whom had received levofloxacin treatment. The treatment had started using IV administration with switch to PO therapy occurring 4 ± 0.81 (mean ± SD) days after therapy, and then remaining on oral therapy for a mean of 4.53 ± 1.56 days. All patients were clinically cured at post-treatment and remained cured at follow-up. The time to delay or disappearance of cough was 10.22 ± 5.35 days; delay to disappearance of chest pain was 5.66 ± 1.96 days; delay to disappearance of purulent sputum was 7.66 ± 4.52 days. No side effects were reported, except for pruritus in one patient, which was possibly related to the antimicrobial treatment. Although this study was limited by its retrospective nature, it provides an indication that levofloxacin is effective as single therapy for mild or moderate CAP caused by L. pneumophila. It also demonstrates that switch to oral therapy is possible by the fourth day and confirms the tolerability and safety of levofloxacin.
The second study that evaluated levofloxacin in CAP caused by L. pneumophila was reported by Dr. R.R. Williams, Janssen-Cilag, Asia-Pacific, Hong Kong in collaboration with researchers from the USA. The study integrated results from three phase III trials and one phase IV clinical trial. Patients in three of the trials received levofloxacin 500 mg once daily for 7-14 days, and in the fourth trial they received the same dose of drug but for 10-14 days. All trials started patients on either IV or oral therapy, with a switch to oral at the investigators discretion. Clinical and microbiological cure was determined 2-5 days after therapy and at follow-up 3-4 weeks after therapy. From all four trials, 1,346 patients were included in the intent-to-treat analysis, with 1,087 clinically evaluable and 742 microbiologically evaluable. L. pneumophila was observed in 4.2% of the CAP cases across the four trials, an incidence similar to that reported in earlier trials. Levofloxacin demonstrated greater than 90% clinical and microbiological success at both post-treatment assessments. Cases were also evaluated according to the severity of their disease. Results showed that 92.1% of the mild/moderate cases were successfully managed, compared to 88.9% of the severe cases at the 2-5-day follow-up (Table 4). Results at the later follow-up were similar. Therefore, similar efficacies were observed in mild/moderate and severe infections. Researchers noted that these results confirm that levofloxacin is an effective therapy for the treatment of L. pneumophila CAP and that this represents the largest study reported to date in which the efficacy of the fluoroquinolones treatment for L. pneumophila CAP has been assessed prospectively.

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Table 4. Clinical and microbiologic responses after levofloxacin treatment in the clinically evaluable population of community–acquired pneumonia patients infected with Legionella pneumophila: stratified according to severity of infection
Table 4
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C. Pneumoniae Emerging as Frequent Cause of Community-acquired RTI

Interest in the role of levofloxacin in treating RTIs caused by some of the less commonly seen pathogens was highlighted by a report which investigated the microbiological efficacy of levofloxacin for the treatment of serious CAP due to C. pneumoniae. Dr. Margaret R. Hammerschlag, State University of New York, Downstate Medical Center, Brooklyn, NY, USA and co-workers noted that C. pneumoniae is a frequent cause of community-acquired RTI, including CAP. However, there has not been a great deal of data in the literature investigating quinolones in the treatment of these infections. In the past, most studies of quinolones for CAP caused by C. pneumoniae have utilized serology for diagnosis, and microbiological efficacy was not assessed. Results of an earlier non-comparative study of levofloxacin for treatment of mild to moderate CAP, with cultures taken for C. pneumoniae, had revealed an eradication rate of 80%. This trial was a randomized, comparative, multicenter treatment of serious CAP, with IV or PO levofloxacin used as therapy. Nasopharyngeal cultures were taken for C. pneumoniae to assess microbiological efficacy. Patients were randomized to receive either levofloxacin 500 mg IV every 24 hrs, switching to PO therapy for a total of 7-14 days. The comparator arm received ceftriaxone 1-2 g IV once daily plus erythromycin 500-1,000 mg IV every 6 hrs, switching to clarithromycin 500 mg PO b.i.d plus amoxicillin/clavulanic acid 875 mg orally twice daily for a total of 7-14 days.
   Patients with serious CAP were enrolled in the study. This was defined as at least three American Thoracic Society (ATS) criteria for admission, or mechanical ventilation or two of the following (fever, hypothermia, respiratory rate > 30/min, systolic blood pressure (SPB) 90mmHg, pulse > 130/min, altered mental status). Nasopharyngeal swabs were taken for C. pneumoniae culture at baseline, 5-7 days after therapy, and 30 days after treatment. Results confirmed that C. pneumoniae was isolated from 22 of 233 patients (9.4%). This pathogen was eradicated in 83% of patients treated with levofloxacin compared to only 67% of patients treated with comparator agents (p = 0.37, Fisher Exact test). Clinically, all C. pneumoniae culture-positive patients were either cured or improved. Only 29.4% of C. pneumoniae culture-positive patients had serologic evidence of acute infection, using revised CDC criteria. Thus, there was a poor correlation between microimmunofluorescence serology and isolation of the pathogen by culture. Over 40% of culture-positive patients were seronegative, confirming that serology cannot be used to determine microbiological efficacy. The researchers concluded that monotherapy with levofloxacin was as effective as combinations of macrolides and beta-lactam antibiotics for eradicating C. pneumoniae from the nasopharynx of patients with serious CAP. This monotherapy was associated with great benefits for levofloxacin, as it was easier to administer, being once daily, with far greater ease in switching from IV to PO therapy compared to the other agents.



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Reduced Risk of Infection Using Levofloxacin for Prophylaxis

A very interesting study was reported by Dr. Michael G. Oefelein, Case Western Reserve University School of Medicine, Cleveland, OH, USA and co-workers, which compared levofloxacin UTI (urinary tract infection) prophylaxis to placebo in men undergoing TRUS (transrectal ultrasound)-guided needle biopsy of the prostate. This is a very common procedure performed for obtaining prostatic tissue to diagnose malignancy of the prostate. It is common to administer antibiotic prophylactically in order to avoid any infectious complications, however there have been limited prospective controlled trials investigating the usefulness of this approach.
   Levofloxacin is considered a good agent to use in this regard as it has excellent penetration into prostatic tissue, peak levels in plasma and prostate occur within one hour of administration, and prostate levels remain high for 24 hrs following a once daily schedule. In this study, 45 patients received levofloxacin 500 mg once daily for three days, with the first dose given 24 hrs before the biopsy. A total of 39 patients were randomized to the placebo arm. Both arms of the study were equal in terms of age, prostate-specific antigen (PSA) values, pre- and post-biopsy IPSS (International Prognostic Scoring System), number of prostate needle cores, or diagnosis on biopsy. Results demonstrated that no levofloxacin-treated patients developed post-biopsy infections. However, four such infections developed in the placebo-treated group. All patients with infection were successfully treated with antimicrobial therapy (three with levofloxacin and one with ciprofloxacin). Thus, without antimicrobial prophylaxis, 4/39 (10%) of transrectal needle biopsies resulted in symptomatic infections, with 5% developing febrile UTIs requiring treatment in the emergency department. In contrast, oral levofloxacin therapy given as three doses significantly reduced the occurrence of symptomatic infections (p < 0.05). The practice of using prophylactic levofloxacin in this setting may be cost-effective by reducing post-biopsy visits, laboratory testing and subsequent treatment. The researchers recommended that further studies be performed looking at the efficacy of one-day versus three-day levofloxacin regimens as well as investigation into the development of any resistant organisms following prophylaxis. This should be performed in tandem with a pharmaco-economic benefit study.



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New Therapy for Anaerobic Infections

While the newer fluoroquinolones in general possess excellent activity against both Gram-negative and Gram-positive pathogens, they have been regarded as having less anti-anaerobic activity. A study reported by Dr. Peter C. Appelbaum et al, Hershey Medical Center, Hershey, PA, USA, investigated the possibility of augmenting this activity by using a fluoroquinolone in combination with other antianaerobic drugs. The agents used in the study were levofloxacin, plus clindamycin or metronidazole, with MICs and synergy time-kill parameters tested against 12 anaerobes. In seven of the 12 strains tested, combining levofloxacin with clindamycin, metronidazole or both compounds led to synergy. This was demonstrated by a reduction in the initial levofloxacin MIC between one- and three-fold. The clinical significance of this synergy was reported to be of particular importance in the Bacteroides fragilis group, which are recognized, along with Enterobacteriaceae, of causing severe intraabdominal infections. While there was no synergy found in Fusobacterium nucleatum, Fusobacterium mortiferum, and Propionibacterium acnes, this may not be of clinical relevance, as levofloxacin possessed a low MIC (0.5-1 mg/ml) against these strains. Although only a small study of 12 strains, researchers concluded that the synergy at sub-MIC levels of levofloxacin when combined with the antianaerobic agents has the potential to expand the antibacterial spectrum of levofloxacin in the treatment of aerobic-anaerobic infections.



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High Dose Levofloxacin Therapy Safe and Effective in Complicated Skin Infections

Not only are fluoroquinolones effective in treating CAP, sinusitis, bronchitis, UTI and pyelonephritis, but their indications have also expanded to encompass uncomplicated and complicated skin and skin structure infections. The latter indication was assessed in a study by Dr. Cynthia L. Fowler, The Robert Wood Johnson Pharmaceutical Research Institute, Raritan, NJ, USA. In order to treat complicated skin infections, high doses of antimicrobials are often required to ensure that a high concentration of drug is made available at the site of infection, even in patients with reduced vascularization. In this trial, 399 subjects were randomized into two arms: Group 1 received levofloxacin, administered at the high dose of 750 mg once daily, while Group 2 were treated with ticarcillin-clavulanic acid IV with or without amoxicillin-clavulanic acid. A total of 138 patients were clinically evaluable in the levofloxacin arm, and of these, 116 (84.1%) achieved clinical success. In contrast, 106 of the 132 clinically evaluable ticarcillin-clavulanic acid group achieved clinical success (80.3%) (95% CI = -13.3, 5.8). Microbiological evaluation was carried out in 98 subjects in both arms, and of these, a bacterial eradication rate of 83.7% was achieved by levofloxacin, compared to 71.4% for the comparator arm (95% CI = -24.3, -0.2). While pseudomonal infections were reported, these only occurred in a small number (six of the seven were eradicated in the levofloxacin arm, and six of the six in the comparator, with clinical success rates similar for both arms).
   The study results were of interest not only for confirming the efficacy of levofloxacin in this situation, but also for clearly demonstrating that levofloxacin can be administered in high doses while maintaining its excellent safety and tolerability profile. The higher dose was not associated with increased toxicity, and in fact the incidence of adverse events was similar for both arms. Gastrointestinal events were the most common for both groups (Table 5). These results support pharmacokinetic data demonstrating that high levofloxacin doses reach peak concentrations that are effective for the treatment of pathogens associated with complicated skin and skin structure infections.

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Table 5. Incidence of frequently reported ( 2%) treatment-emergent side effects, regardless of relationship to study medication: safety was evaluated for the entire intent-to-treat population
Table 5
a One subject inadvertently entered the study twice. For efficacy, this subject was included only in the first treatment group (comparator antibiotics), but for safety, he was included in both treatment groups.
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Clarifying the Issue of Fluoroquinolone Penetration into Cerebrospinal Fluid

Levofloxacin is known to possess activity against Gram-negative organisms, including the most often responsible for meningitis (H. influenzae, Neisseria meningitidis, E. coli) and also has excellent efficacy against S. pneumoniae, and less commonly involved central nervous system (CNS) pathogens, such as M. pneumoniae, C. pneumoniae and Rhodococcus equi. However, fluoroquinolones have not been advocated for use in meningitis, due to a lack of evidence for penetration into the CNS tissues. However, animal studies have now demonstrated that in an experimental meningitis model, levofloxacin had extensive passage through an altered blood brain barrier.
The cerebrospinal fluid (CSF) penetration of levofloxacin during cotreatment for bacterial meningitis was investigated by Dr. Federico Pea, Institute of Clinical Pharmacology and Toxicology, University of Udine, Udine, Italy, in five patients with clinically confirmed meningitis. (Dosage administered was 500 mg b.i.d. in four cases, 500 mg once daily in one case) and this was added to a standard beta-lactam regimen. Four causative pathogens were identified (S. pneumoniae in two cases, E. coli and N. menigitidis in one case each). All were sensitive in-vitro to levofloxacin. The mean levofloxacin plasma levels before dosing, 0.5hr, and 2hr post-dose were 1.34µg/ml, 8.16µg/ml, and 5.93µg/ml, respectively. The average levofloxacin concentration in the liquor compared to plasma at 2hr was 0.34µg/ml. Further investigation into these levels revealed that levofloxacin penetration was higher in subjects with greater meningeal inflammation. This finding was in contrast to previous views, which held that due to its lipophilicity, fluoroquinolone penetration into CSF would be minimally affected by inflammation. All patients recovered with no adverse events at 30 days follow-up, and this indicates that levofloxacin 500 mg b.i.d. used in combination therapy could be useful in treating bacterial meningitis caused by H. influenzae, N. meningitidis, E. coli and other Enterobacteriaceae.

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Safety Update - How the Fluoroquinolones Differ

The question facing the clinician now is which fluoroquinolone to use. Deciding upon an individual agent can be difficult, although the latest data now available can aid the physician in making a rationale choice. With the newer fluoroquinolones now seen as having excellent efficacy against many pathogens, it has become increasingly recognized that they can best be differentiated from each other based upon safety features. This has become important with the recognition that some of the previous agents, such as trovafloxacin, temafloxacin and sparfloxacin, had unacceptable side effects. One major cause for concern was related to the cardiotoxicity of fluoroquinolones. It was therefore very timely that results from a comparative study were reported by Dr. Takehiro Hagiwara et al., New Drug Research Laboratories II, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan. This study investigated the cardiac action potentials recorded following administration of fluoroquinolones, using tissue strips dissected from right ventricular walls of guinea pigs. These were electrically stimulated using rectangular pulses, and the cardiac action potentials were recorded. After becoming stabilized, 2µl, 18µl and 180 µl of the 10mM stock solution of test compounds were cumulatively added to the bath solution, achieving a final concentration of 1µM, 10µM, and 100 µM respectively. The resting membrane potentials, action potential amplitudes, overshoot action potential duration (APD) at 20%, 50% and 90% repolarization and maximum rate of rise of action potential were calculated.
   The fluoroquinolones evaluated in the study included sparfloxacin, moxifloxacin, grepafloxacin, gatifloxacin, tosufloxacin, gemifloxacin, ciprofloxacin, trovafloxacin, sitafloxacin, and levofloxacin. The effects of the 10 fluoroquinolones on APD90 at differing concentrations are shown in Figure 2. APD90 at 100µM was lengthened following administration of sparfloxacin, moxifloxacin, grepafloxacin, and gatifloxacin by 40.8%, 25.1%, 23.8%, and 12.7% respectively. This was in sharp contrast to levofloxacin, which had little, if any effect on APD90 at all concentrations up to 100µM (0.8% change only). There was little effect on APD90 seen for tosufloxacin, gemifloxacin, ciprofloxacin, trovafloxacin and sitafloxacin, although all of these agents caused greater change than that of levofloxacin (5.2%, 4.2%, 3.3%, 2.9%, 2.4% respectively). Dr. Hagiwara concluded that these results clearly demonstrated that there are marked differences in the potential of individual fluoroquinolones to cause cardiac toxicity through changes in electrical conduction. Those with high potential for causing APD-prolongation effects include gatifloxacin, moxifloxacin, grepafloxacin, and sparfloxacin, while levofloxacin was the least likely agent to cause this problem.
   Another important study adding further information about the toxicity profiles of different fluoroquinolones was presented by Dr. Koji Shimoda, Drug Safety Research Laboratory, Daiichi Pharmaceutical Co. Ltd., Tokyo, Japan, who performed a comprehensive review of clinical trials, case reports and post-marketing surveillance of quinolones during 1993-2000, leading to the investigation of photosensitivity incidence associated with 13 individual fluoroquinolones in-vivo in mice. The study protocol involved a single intravenous injection of a fluoroquinolone at 5mg/kg, 10mg/kg, 20mg/kg, 40mg/kg, and 80 mg/kg doses. Mice were then irradiated for 4 hr, after which their ears were measured for changes in thickness and the development of auricular erythema. Laboratory evaluation included the measurement of prostaglandin (PG) release from fibroblasts following treatment with a quinolone plus or minus ultraviolet A (UVA) irradiation. Definite differences among the fluoroquinolones were observed, with levofloxacin having an exceptionally low phototoxicity rate of 0.1%. This was markedly lower than that for sparfloxacin (0.4-7.9%); fleroxacin (< 0.6%), clinafloxacin (2.4%), and tosufloxacin (0.1-0.2%) and was equivalent to enoxacin, ciprofloxacin, ofloxacin, norfloxacin, moxifloxacin, grepafloxacin, and trovafloxacin. A single IV dose of levofloxacin up to 80 mg/kg plus UVA irradiation did not induce phototoxic changes (Table 6), and using a dose of 100µM plus irradiation did not affect prostaglandin levels. In contrast, treatment with sparfloxacin markedly increased the concentration of PGE2 and 6-keto-PGF1alpha levels. Researchers concluded that the phototoxic potential of levofloxacin is very low, and is markedly less than that developing following administration of sparfloxacin, lomefloxacin, fleroxacin, clinafloxacin and enoxacin.


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Figure 2. Effects of 10 fluoroquinolones on APD90 at concentrations 0–100µM.
Figure 2
Each point and vertical bar represent the mean ± standard error (n = 4–6).
* p < 0.05, ** p < 0.01: significantly different from the initial value by paired t–test.
Abbreviation: APD = action potential duration.


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Table 6. Phototoxic potential of quinolones in female BALB/c mice
Table 6
Abbreviations: ND = not detected, BALB/c = bagg albinos/c.
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Last updated January, 2003