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toumei ../image Congress Report

The 22nd International Conference of Chemotherapy
June 30-July 3, 2001 Amsterdam, The Netherland

CONTENTS

Introduction

Criteria for the Choice of Antimicrobial Agent: Examining the Balance Between Efficacy, Safety and Tolerability.

Drug-Drug Interactions With Levofloxacin: Tolerance and Contraindications

Levofloxacin Safety Update Focusing on Cardiotoxicity

Surveillance Studies Allow the Physician to Monitor Changing Resistance Trends

Clinical Advantages Associated With Levofloxacin Over Cefaclor and Cefuroxime

Overwhelming Safety of Levofloxacin Confirmed

QOL Improves Faster When Using Levofloxacin in URTI

Levofloxacin - Possesses Clinical Efficacy As Well As Immunomodulatory Functions


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Introduction

The 22nd meeting of the biannual International Congress of Chemotherapy was held in Amsterdam, from June 30-July3, 2001. Congress President, Dr. Jan Verheof, commented on the need for compassion in medicine, and for physicians to restrain from focusing solely upon the latest technological advances at the expense of all-round patient care. This key message was highlighted by the congress slogan: "Compassion and Science". Bringing together these strands of medical knowledge was new research data that reported not only efficacy results but also placed a strong emphasis on safety. Patients must be effectively managed, but this has to be balanced with a clear need for well-tolerated therapies. New antimicrobials are constantly being developed, and clinicians are bombarded with new drug options. However, the latest is not always the best and we all need to use an evidence-based approach with clearly defined outcomes in terms of both efficacy and safety. One of the most useful fluoroquinolones in this regard is levofloxacin. It has a huge post-marketing database, which has clearly demonstrated this very effective agent to also be extremely safe. Presentations from the meeting that focus upon this agent are summarized below.


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toumei ../image Criteria for the Choice of Antimicrobial Agent: Examining the Balance Between Efficacy, Safety and Tolerability.

An informative symposium co-chaired by Dr. Andy Hoepelman, Head of Department of Acute Medicine and Infectious Diseases, Professor of Department of Medicine, University Medical Center Utrecht, Utrecht, The Netherlands and Dr. Ethan Rubinstein, Professor of Department of Internal Medicine and Unit of Infectious Diseases, Tel Aviv University School of Medicine, Tel Aviv, Israel. Dr. Hoepelman noted that choosing the best antimicrobial for specific situations must be based on a balance between efficacy, safety and tolerability. This requires an awareness of the most likely pathogens for the specific infection and region. Thus, in community-acquired pneumonia (CAP), the physician first needs to consider that the infection is caused by Streptococcus pneumoniae, Mycoplasma pneumoniae, Haemophilas influenzae, Chlamydia pneumoniae. In more severe cases, Legionella spp., Gram-negative bacilli, Staphylococcus aureus and Pseudomonas aeruginosa also become more likely as causative pathogens. Levofloxacin offers the advantage of an expanded spectrum of activity, with proven efficacy against the majority of these pathogens, including important atypicals. It is also effective against penicillin resistant S. pneumoniae(PRSP), a pathogen that is causing increasing concern around the globe.
Pharmacokinetic features of individual antimicrobials also contribute to their safety profile, and thus need to be assessed when prescribing. Specific pharmacokinetic/pharmacodynamic (PD) evidence relating to the safety of the fluoroquinolones was reported by Dr. William A. Craig, Professor of Department of Medicine, University of Wisconsin, Madison, WI, USA who summarized PK as being concerned with the absorption, distribution and elimination of antimicrobials. The bioavailability of respiratory fluoroquinolones is very high, particularly for levofloxacin at 99%, compared to only 70% for grepafloxacin. The long half-life of these agents allows for once-daily administration, and levofloxacin with exceptional bioavailability can be easily switched from intravenous(IV) to oral(PO) form. Fluoroquinolones are effective and comparable to standard agents in the management of CAP.
Included in this symposium were results presented by Dr. Javier Garau, Head of Department of Medicine, Hospital Mutua de Terassa, Associate Professor of Medicine, University of Barcelona, Barcelona, Spain, who compared ADRs associated with fluoroquinolones with those occurring with other antimicrobials. He noted that there is a very low frequency of abnormal liver function tests associated with levofloxacin administration, none of which have required discontinuation of therapy. Fluoroquinolones as a class are associated with a 2-20% incidence of gastrointestinal(GI) ADRs, with nausea and vomiting occurring at similar rates to comparators such as beta-lactams and macrolides, although diarrhea occurs more frequently with beta-lactams. The rate of diarrhea associated with levofloxacin is 1.2%, nausea 1.2%, and vomiting 0.2%. The estimated rank order of GIADRs among the quinolones is grepafloxacin > trovafloxacin> sparfloxacin > pefloxacin > ciprofloxacin > levofloxacin > norfloxacin > ofloxacin.
Dr. Garau noted that central nervous system AEs are the second most common side effect associated with fluoroquinolone administration, occurring in 1-2% of patients. The majority of these are mild, including dizziness, and it is important to note that this side effect has not been reported for levofloxacin. More serious CNS effects usually occur in those patients taking concomitant theophylline or NSAIDs, as these agents interfere with the GABA pathway and result in an increased likelihood of adverse events. Levofloxacin has been shown to have a very low interaction potential with these agents, and thus is less likely than many other fluoroquinolones to be associated with CNS events. The estimated rank order in CNS AEs is trovafloxacin > grepafloxacin > norfloxacin > sparfloxacin> ciprofloxacin > ofloxacin > pefloxacin > levofloxacin which has an extremely low incidence of CNS AEs (0.2-1.1%). Several studies have shown that the binding of fluoroquinolones to the brain GABA receptors correlates with their epileptogenic properties. An assessment of individual fluoroquinolones has demonstrated that levofloxacin is the least likely to result in GABA receptor binding, and thus has the lowest potential for initiating CNS ADRs. In addition, levofloxacin is less likely to be influenced by concomitant NSAID, which has been shown to enhance the epileptogenic effect of ciprofloxacin. Thus, Dr. Garau noted in conclusion that among the fluoroquinolones, the greatest database has been built up for levofloxacin, with most recent reports showing that at more than 200 million prescriptions worldwide, this agent is extremely safe for physicians to prescribe.


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toumei ../image Drug-Drug Interactions With Levofloxacin: Tolerance and Contraindications

The symposium continued with an in-depth look at drug-drug interactions, which can be an important clinical consideration with the fluoroquinolones, according to Dr. Enrico Mini, Associate Professor of Chemotherapy, Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy. Dr. Mini stressed that due to the extensive use of fluoroquinolones, especially in older patients with significant co-morbidity, on many occasions fluoroquinolones are administered concomitantly with other agents. Clinically significant interactions with potential agents can be PK, affecting either the absorption, elimination or metabolism of the drug. On the other hand, the interaction may be PD, with either opposition or potentiation of the effects of other agents.
There is a wealth of data outlining reductions in absorption of the fluoroquinolones when taken with a number of agents. The most clinically important of these is the interaction with antacids, as they are often self-administered by many patients. In addition, sucralfate, iron preparations, didanosine, cytotoxic chemotherapy, activated charcoal, and ranitidine have been reported to interact with some of the fluoroquinolones. Research carried out to clarify the interaction between levofloxacin and antacids demonstrated that when magnesium and ferrous compounds were administered with levofloxacin there was a drop in absorption of the antimicrobial. However, levofloxacin values were only slightly changed when administered with calcium carbonate and ranitidine. A potential interaction with sucralfate was evaluated, and results confirmed that levofloxacin administered 2hr later was associated with no significant variation in plasma concentrations over time. Thus, by modifying the timing of administration, an important drug interaction can be avoided.
   Reduced elimination, which can lead to increased concentration of a drug and consequent potentiation of effect, may be due to changes in renal metabolism (as illustrated by probenecid, cimetidine, beta-lactams) or via altered metabolism. The metabolization of an agent can also be changed, and this has been shown to occur with theophylline, phenytoin, warfarin, cyclosporin, digoxin, opioids, chlorpropamide, glibenclamide, and metoprolol. In some circumstances this is due to inhibition of cytochrome P450 isoenzymes, as is the case with theophylline and caffeine, which are both extensively metabolized via this enzyme system in the liver. If a fluoroquinolone inhibits this activity, it can result in increased theophylline levels, which is associated with ADRs including tachycardia, nausea and seizures. Dr. Mini cited a report by Niki et al., which used clinical and pharmacological data to classify fluoroquinolones into three groups according to the degree of their theophylline interaction. Agents listed as belonging to Group I are associated with a very high risk of inducing toxic effects. They do this by causing a > 40% increase in Cmax and AUC values for theophylline. Agents belonging to Group II including pefloxacin, ciprofloxacin, tosufloxacin and grepafloxacin are associated with a 15-40% increase in theophylline levels, causing moderate ADRs. However, those agents in Group III such as trovafloxacin, norfloxacin, ofloxacin, sparfloxacin, and levofloxacin have no significant interaction with theophylline. This is highlighted by the fact that there is no significant change in PK parameters when theophylline is administered IV following a 500mg dose of levofloxacin.
   Warfarin is another commonly prescribed agent, and one that has been reported to interact with some fluoroquinolones. A double-blind, randomized placebo controlled trial designed to evaluate whether this is a significant interaction for levofloxacin 500mg, revealed no PK/PD variations in warfarin values. In addition, a study investigating multiple doses of levofloxacin 500 mg b.i.d. concomitantly with oral cyclosporin revealed no changes in the pharmacodynamic profile.
   Of particular concern is any interaction between fluoroquinolones and agents that prolong the QTc interval, which can result in an increased incidence of cardiovascular complications. This is of concern for moxifloxacin and gatifloxacin, which both have the potential to interact with medications causing QTc interval prolongation, but this does not appear to be the case with levofloxacin (Table 1). Thus, in summarizing his talk, Dr. Mini noted that the drug-drug interaction profile for levofloxacin compares favorably with that of other quinolones, and only minor precautions need to be taken with regard to timing with antacids.


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Table 1. Clinically relevant drug interactions with fluoroquinolones

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toumei ../image Levofloxacin Safety Update Focusing on Cardiotoxicity

The problem of cardiotoxicity was further addressed by Dr. Ethan Rubinstein, who noted that QTc prolongation associated with levofloxacin is a very rare event occurring in less than 1 per million. In contrast, this cardiovascular ADR occurs at a rate of 14.5 per million for sparfloxacin. Therefore, there is a clear difference among the individual fluoroquinolones with regard to their propensity to cause cardiac ADRs. Basic research has indicated that the strength of the fluoroquinolone QTc prolongation effect is correlated with their potassium antagonist action, with sparfloxacin and grepafloxacin having a high affinity for such antagonists. This results in their having a greater potential for causing ventricular tachycardia (Table 2). While QTc prolongation is probably a fluoroquinolone class effect, there is a 10-15-fold difference in ability to cause this among the individual fluoroquinolones. Dr. Rubinstein noted that if the patient does not have an inborn prolonged QTc interval syndrome, or does not receive antiarrhythmics causing QTc prolongation, levofloxacin appears to have no clinically relevant cardiotoxicity.


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Table 2. QTc interval effects with fluoroquinolones

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toumei ../image Surveillance Studies Allow the Physician to Monitor Changing Resistance Trends

Surveillance of global resistance patterns is now universally seen as extremely important data, allowing the physicians to prescribe antimicrobials tailored to their own environment. Results from a major ongoing surveillance study were reported, providing insights into changes in bacterial susceptibility. Results for the 1999-2000 respiratory season were presented by Dr. Mark E. Jones, Associate Director, Focus Technologies, Inc., Hilversum, The Netherlands, and colleagues. The researchers looked at levofloxacin activity among 4,998 S. pneumoniae isolates, including resistant phenotypes. While penicillin and macrolide resistance varied considerably around the world, the activity profile of levofloxacin was maintained with resistance to levofloxacin less than 1% in 8 countries (United Kingdom, Thailand, Germany, France, Brazil, Italy, South Korea and South Africa), 1.5% in Mexico, 1.6% in Spain, 3.3% in China and 8.0% in Hong Kong. Further investigation of these higher Asian values revealed clonal spread within specific institutions to be responsible (Table 3). In contrast, penicillin resistance ranged widely to a high of 70.1%, azithromycin resistance ranged from 4.7-85.5% and the problem of trimethoprim-sulfamethoxazole (TMP-SMX) resistance was noted with rates of 4.8-69.5%. In addition, 12.5% of the isolates had MDR phenotypes, whereas those that included levofloxacin were rare (4.0%). Researchers confirmed that levofloxacin was the most active agent among those tested (comparator agents included penicillin, ceftriaxone, azithromycin, TMP-SMX), with less than 1% of all isolates showing resistance.


  Table 3. Antimicrobial susceptibilities of Streptococcus pneumoniae collected during the 1999–2000 respiratory season
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Clinical Advantages Associated With Levofloxacin Over Cefaclor and Cefuroxime

Clinical efficacy of levofloxacin in a wide range of infections has been shown in a number of clinical studies. However, its primary focus of use remains respiratory tract infections, with excellent activity over the majority of pathogens responsible for these infections. One report from the Congress provided a comparison of levofloxacin versus cefaclor and cefuroxime in the management of acute exacerbations of chronic bronchitis (AECB). Dr. Iain Simpson and Dr. Ian Harding, Micron Research, UK, reported data on the prevalence of beta-lactam-, macrolide- and fluoroquinolone- resistance among S. pneumoniae, H. influenzae and Moraxella catarrhalis obtained from the Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin (PROTEKT) database, which is an interactive internet-based database, from a worldwide surveillance study of the susceptibility of respiratory tract pathogens to antibiotics. This confirmed high levels of resistance to macrolides and beta-lactams among the major AECB pathogens. In contrast, levofloxacin resistance was less than 2% among S. pneumoniae and was not detected among H. influenzae and M. catarrhalis (Table 4). This corresponded to excellent clinical efficacy for levofloxacin in managing AECB, with clinical success and bacteriological eradication rates being at least as high as cefaclor and cefuroxime axetil. The researchers noted that these results, coupled with its very convenient once-daily PO dosing schedule, favor levofloxacin as a treatment for patients with AECB.
The efficacy and tolerability of levofloxacin relative to the beta-lactams and macrolides was further assessed in both the treatment of CAP and acute sinusitis by the same researchers. They found that a review of outcome data from four large clinical trials in patients with CAP of varying severity suggested that levofloxacin was effective for treating patients with all grades of CAP, including those with bacteremia, penicillin-resistant pneumonia or atypical infections. In fact, the clinical (93.7%) and bacteriological (93.5%) success rates were very high, and superior to the pooled comparator results (Figure 1). Comparators included amoxicillin-clavulanic acid, ceftriaxone and cefuroxime axetil.
In the sinusitis section, the authors noted the confirmed increase in the spread of beta-lactam and macrolide resistance among S. pneumoniae and H. influenzae, the most common pathogens responsible for acute sinusitis. This is of particular concern in Southeast Asia and some parts of Europe. In contrast, the very low incidence of levofloxacin resistance is reflected in the high clinical (87.9%) and bacteriological (87.1%) success rates in clinical sinusitis trials. Comparative trials confirmed the efficacy of levofloxacin, thereby showing it to be at least equivalent in efficacy to clarithromycin, or amoxicillin-clavulanic acid and clarithromycin. Thus, levofloxacin was shown to be an effective, well-tolerated and more convenient treatment compared to alternatives currently available in the empiric treatment of acute sinusitis.


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Table 4. Summary of MIC data and susceptibility analysis obtained from PROTEKT (online analysis 27 April, 1999)


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Figure 1. Clinical success with levofloxacin and comparator treatments (Studies1–4).

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Overwhelming Safety of Levofloxacin Confirmed

A review of the tolerability and safety of levofloxacin was undertaken by Dr. Iain Simpson and Dr. Ian Harding, Micron Research, Upwell, Cambs, UK. These researchers noted that the fluoroquinolones can no longer be lumped together in terms of safety, and that marked differences are now emerging among the individual agents. This has been made even more apparent with the withdrawal of several of these compounds due to unacceptable ADRs, which include hepatotoxicity, cardiotoxicity, and phototoxicity. This study evaluated the safety of levofloxacin, utilizing data from 28 clinical pharmacology studies, 19 phase III studies, 22 post-registration intensive monitoring studies and post-marketing experience drawing on more than 100 million prescriptions.
   The most often reported ADRs associated with levofloxacin administration included nausea (4.9%), diarrhea (4.5%) and headache (4.1%). These values were very similar to those found for comparator agents (4.8%, 7.9% and 4.5%, respectively). The incidence of serious ADRs was similar for levofloxacin and comparator agents (5.5% and 5.0%, respectively) although the discontinuation rate associated with levofloxacin was slightly lower in regulatory studies than that seen with comparators (3.8% versus 4.5%). There was also a very low incidence of deaths reported in patients taking levofloxacin (1% versus 1.3% for comparators), with none of the deaths demonstrated to be caused by the drug.
   Interest in hepatotoxicity associated with the fluoroquinolones has mounted with the recognition of problems caused by trovafloxacin. Results from this review confirmed levofloxacin to be very safe in this regard, with serious ADRs related to the hepatic system reported in less than 1%, irrespective of any causal relationship. In fact there were no reports of liver serious ADRs possibly related to levofloxacin (Figure 2). From post-marketing surveillance (PMS) utilizing data from 67 million prescriptions, only 190 cases relevant to hepatic or biliary systems have been identified. In the cases where hepatic ADRs have been reported, there has been no convincing evidence of a causal relationship with levofloxacin, and in most of the more serious ADRs alternative causes are likely to be responsible. These include other medications, underlying disease and pre-existing conditions.
   Cardiotoxicity is another specific ADR that has generated some concern in regard to fluoroquinolone administration. However, in this large evaluation there were no instances of QTc prolongation or torsades de pointes associated with levofloxacin. All reported clinically significant cardiac events occurred in patients with underlying disease and/or those taking other medications known to affect cardiac conduction. The presenters concluded that all of the available data confirmed levofloxacin to be a well tolerated antimicrobial, with no significant effects on hepatic or cardiovascular systems, with a high benefit to risk ratio.


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Figure 2. Comparison of possible hepato- and drug related severe adverse events (SAEs) in levofloxacin and comparator treated patients. Numbers represent number of patients in each category.

Numbers represent number of patients in each category.
Abbreviation: severe ADRs = severe adverse drug reactions.
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QOL Improves Faster When Using Levofloxacin in URTI

Levofloxacin was compared with cephems in the treatment of acute upper respiratory tract infections (URTI) with 279 patients receiving cephems, and 754 treated with levofloxacin. Dr. Hisashi Moriguchi, Associate Professor at the Research Center for Advanced Science and Technology, University of Tokyo, Tokyo, Japan performed a study aimed at overcoming the limitations of other URTI trials, which often do not carry out bacteriological evaluation nor measure days until cure. This study provided a more evidence-based approach to this common therapeutic problem, and used reduction in temperature to assess when therapy had succeeded. All subjects had a temperature of > 38.6 ºC at the start of therapy. Treatment with levofloxacin resulted in a significantly higher cure rate than cephems when based on body temperature, and this was even more apparent for the patients with tonsillitis. This high rate of cure associated with levofloxacin occurred with or without concomitant NSAID administration. In contrast, the cure rate of cephems was reduced when NSAIDs were not administered concurrently. An assessment of QOL also revealed that levofloxacin treated patients showed a significantly better improvement on the fifth day compared to cephems (Figure 3). In addition to faster efficacy, and being associated with greater QOL as assessed by the patients, levofloxacin was also associated with a lower incidence of ADRs compared to cephems (0.4% versus 1.2%). Thus, levofloxacin was described as a better choice than cephems in the treatment of URTI in patients with a fever of > 38.6 ºC


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Figure 3. Comparison of quality of life assessment among patients treated with levofloxacin and those treated with cephems.
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Levofloxacin - Possesses Clinical Efficacy As Well As Immunomodulatory Functions

The excellent efficacy of levofloxacin has been shown to be enhanced by its ability to improve a patient's immunomodulatory function. A study reported by Dr. Noboru Yamanaka et al., Department of Otolaryngology-Head and Neck Surgery, Wakayama Medical University, Wakayama, Japan, assessed the effect of levofloxacin on the production of IL-1alpha, IL-1beta, IL-8, IL-12, IFN-gamma, and TNF-alpha by tonsillar mononuclear cells and nasal mucosa. In addition, the researchers quantified the production of cytokines from normal nasal mucosa, tissue stimulated by staphylococcal enterotoxic B (SEB) and SEB stimulated tissue treated with either 5µg/ml or 50µg/ml levofloxacin.
   TNF-alpha production was suppressed in both the 5µg/ml and 50µg/ml levofloxacin groups (p < 0.01) (Figure 4), with the suppression greatest in the 48-hour group of the 5µg/ml levofloxacin arm. It was also reported that IFN-gamma production was suppressed in both the 24- and 48-hour 50µg/ml levofloxacin groups, while IL-8 was markedly suppressed in the 24-hour group treated with 5µg/ml levofloxacin. Dr. Yamanaka drew the audience's attention to the fact that cytokine production was suppressed by the 5µg/ml dose of levofloxacin, noting that this is a clinically achievable dose. No effect was shown on IL-1alpha, IL-1beta or IL-12 production. These results demonstrate that levofloxacin has immunomodulatory effects acting on tonsillar lymphocytes, by suppressing proinflammatory cytokines.
They then looked at the effect of levofloxacin on regulated upon activation, normal T-cell expressed and secreted (RANTES) release from nasal epithelial cells, as it has been proposed that RANTES released from these cells might be a pivotal factor in eosinophilic infiltration which occurs in allergic rhinitis. Thus, the aim was to investigate whether levofloxacin had an immunomodulatory effect on this release. Nasal cells were cultured in the presence of SEB, SEB plus 5µg/ml levofloxacin and 50µg/ml, as well as a control. It was clearly demonstrated that in the unstimulated control only small amounts of RANTES were released. However, this release was significantly stimulated by SEB. When levofloxacin was added to this, 30% of subjects had inhibition of RANTES release. This suppression of RANTES release by levofloxacin may play an immunomodulatory role in patients with chronic sinusitis, and can only provide an additional benefit for the physician and patient when using this agent.


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Figure 4. Effect of levofloxacin on TNF-alpha production.
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