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Highlights from the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy
Toronto, Canada, September 17-20, 2000

CONTENTS

Introduction

Resistance - Where We Stand

Penicillin Resistance Decreasing in Canada - Is It Real?

Ciprofloxacin Use Associated with Quinolone-Resistant Gram-Negative Bacilli

Safety of the Fluoroquinolones - Effect of Individual Agents Clarified


Phototoxic Potential Clarified

Convulsions - Which Fluoroquinolones Are Responsible?

Tendon and Joint Effects

Hepatic Toxicity - Which of the Fluoroquinolones are Affected?

Cardiac Toxicity - Levofloxacin Safer than Other Fluoroquinolones

Guidelines - Should They Be Used in Community-Acquired Pneumonia?

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Introduction

The 40th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) was held in Toronto from September 17-20, 2000. Recognized as one of the most influential infectious disease meetings, ICAAC acts as a conduit of latest trends and developments in this rapidly changing area. One of the major themes discussed at ICAAC was antibacterial resistance. International surveillance data providing comprehensive information on the current resistance situation internationally were reported. Safety was another very important issue, particularly in regard to the fluoroquinolones which are now the most commonly prescribed oral antimicrobials in the United States. Levofloxacin, one of the major fluoroquinolones, has wide-ranging activity covering all of the most common and atypical respiratory pathogens, as well as excellent pharmacological features which make it a favorite for managing respiratory infections. These highlights summarize the latest findings relating to these important themes.

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Resistance - Where We Stand

Dr. Daniel F. Sahm, MRL Pharmaceutical Services, Inc., Herndon, VA, USA, reported results of recent Streptococcus pneumoniae susceptibility data from the TRUST II and TRUST III. This data demonstrated that the percentage of penicillin-resistant S. pneumoniae (PRSP) increased from 12.3% in the 1997-98 year to 14.7% in the following year. Resistance to ceftriaxone was noted, while azithromycin resistance increased from 20.9% to 22.7%. Of concern, was the rapid rise in resistance among the pneumococcus to trimethoprim-sulphamethoxazole (TMP-SMX) which has risen from 13.8% to 27.3%. Levofloxacin resistance remained very low, with latest TRUST IV data from the 1999-2000 year showing this had reduced to 0.5%.

Multidrug-resistant (MDR) strains among S. pneumoniae increased from the 6.2% seen in 1997-98 to 11% the following year (Table 1). Resistance continues to increase in all clinically relevant bacterial species, highlighting the need for ongoing surveillance.

Table 1. Characterization of multidrug-resistant phenotypes of Streptococcus pneumoniae (1997-2000)

Table1

Risk factors associated with antimicrobial resistance among S. pneumoniae in the US were investigated. Ceftriaxone, azithromycin and TMP-SMX resistance was significantly higher in the younger age group (less than 15 years) compared to other age groups. No levofloxacin-resistant strains were found in this patient group. Ceftriaxone, clarithromycin, and TMP-SMX resistance was significantly higher among the PRSP strains (p < 0.001). In contrast, levofloxacin resistance was similar for both penicillin-resistant and penicillin-susceptible strains (0.5% and 0.3%, respectively).

S. pneumoniae exhibited an increase in resistance over the three years to all antimicrobials tested except vancomycin (no resistance) and levofloxacin (decrease from 0.6 to 0.5% in 1998-99 and 1999-2000 (Table 2). Levofloxacin resistance among respiratory isolates (0.6%) was fivefold lower than ceftriaxone resistance and nearly 40-fold lower than azithromycin and TMP-SMX.

Table 2. Comparative resistant rates among Streptococcus pneumoniae over 3 yearsa

Table2

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Penicillin Resistance Decreasing in Canada - Is It Real?

The importance of looking at all data was emphasized by reports from Canada which show a decreasing incidence of penicillin-resistant and MDR S. pneumoniae over the three-year period 1997-2000. Dr. Daryl J. Hoban, et al., Health Science Centre, Winnipeg, MB, Canada, looked at over 3,500 respiratory tract S. pneumoniae isolates. Results confirmed that penicillin-susceptible S. pneumoniae (MIC < 0.06 µg/ml) have increased in Canada over the study period from 78.8% to 80.4%, with latest figures now at 85.6%. In addition, the penicillin non-susceptible S. pneumoniae have stabilized or decreased over the same time, and the MDR S. pneumoniae rate has also decreased as penicillin resistance has decreased. These results are the first documented evidence of decreasing resistance to penicillin and need to be followed to confirm if this trend is real and continuing.

In contrast to the Canadian results, international data from the Alexander Project, reported increasing penicillin resistance among S. pneumoniae. The prevalence of penicillin-intermediate (MIC 0.12-1µ/ml) and PRSP strains varied between countries, although several countries had more than 50% of their isolates identified as non-susceptible (Israel, South Africa, Saudi Arabia, Hong Kong, Japan, Singapore, Mexico and France). The US also had high resistance rates, with only 59% of their isolates susceptible to penicillin. Macrolide resistance was also high with more than 30% of resistance in the US, Hong Kong, Singapore, Japan, France, Italy and Spain.

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Ciprofloxacin Use Associated with Quinolone-Resistant Gram-Negative Bacilli

The potential of different quinolones to result in resistant mutants was investigated by Dr. B. N. Hota, Rush Medical College, Chicago, USA, who assessed the effect of substituting ciprofloxacin with levofloxacin in a medical intensive care unit. During the levofloxacin-treatment period, 12% of patients were colonized with quinolone-resistant Gram-negative bacteria (QRGNB) on admission, with 90 receiving follow-up investigation. 30% of these patients were treated with levofloxacin, and only 15% of these patients acquired QRGNB, compared to 6.5% for those not treated with levofloxacin. These results show that although there was no significant difference in QRGNB carriage at the beginning of both time periods, ciprofloxacin treatment was more likely to result in QRGNB than levofloxacin.

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Safety of the Fluoroquinolones - Effect of Individual Agents Clarified

Since their introduction in the 1960s, quinolones have changed greatly. By changing constituents attached to the quinolone ring, they have gained activity over a number of pathogens, and incorporated changes to their pharmacological features. With ongoing development of the fluoroquinolones, more data has become available detailing specific relationships between structure and both activity and toxicity. An overview outlining the association between structure and side effect profiles was presented by Dr. Kenichi Sato, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.

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Phototoxic Potential Clarified

Levofloxacin and ciprofloxacin were confirmed to have a much lower potential for inducing phototoxicity than sparfloxacin, lomefloxacin and enoxacin. These results are confirmed by Phase IV data detailing that sparfloxacin is associated with a very high rate of photosensitivity of 1 in 189. Levofloxacin is at the other end of the spectrum, with a proven safety record in this regard, having a photosensitivity rate of just 1 in 200,000 patients.

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Convulsions - Which Fluoroquinolones Are Responsible?

A study evaluating the dose of individual fluoroquinolones required to induce 80% incidence of clonic convulsions in mice found that levofloxacin was among the least likely agents to cause convulsions, particularly when co-administered with NSAIDs (Table 3). In contrast, the ability of enoxacin to cause convulsions was dramatically increased when biphenyl acetic acid was co-administered. Phase IV results also support the safety of levofloxacin showing that the incidence of clonic convulsions caused by levofloxacin alone was 1 in 250,000. When levofloxacin was used in combination with NSAIDs, this increased only to 1 in 53,000.

Table 3. Dose of new quinolones required to produce 80% incidence of clonic convulsions in mice (mg/kg)

Table3

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Tendon and Joint Effects

Tendon cytotoxicity was investigated by Dr. F. Pouzaud and colleagues, Unité Pharmaco Toxicologie Celluaire, Paris, France. They evaluated oxidative stress and cell death mechanism of five fluoroquinolones (pefloxacin, ciprofloxacin, moxifloxacin, levofloxacin and ofloxacin) directly on rabbit tenocytes. Their results confirmed that agents causing high tenotoxicity were pefloxacin, moxifloxacin, and ciprofloxacin. In contrast, ofloxacin and levofloxacin, were associated with low tenotoxicity.

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Hepatic Toxicity - Which of the Fluoroquinolones Are Responsible?

FDA data shows that 140 cases of serious hepatopathy were reported for trovafloxacin from 2.5 million patients treated over a six-month period, resulting in an incidence rate of 1 in 1,800. In comparison, levofloxacin has an excellent safety record. A total of 88 million patients had been treated with levofloxacin in Japan with only 87 serious hepatic reactions reported, giving an extremely low incidence of 1 in 100,000.

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Cardiac Toxicity - Levofloxacin Safer than Other Fluoroquinolones

Evidence is now available to show that there are marked differences between individual quinolones in causing cardiac adverse events such as QTc prolongation. Research into myocardial conduction revealed significant differences among the quinolones with sparfloxacin causing a 40% change in action potential duration at 90% of repolarisation (APD90) while a new fluoroquinolone, sitafloxacin, did not show any elongation. When higher doses of drug were used, levofloxacin, sitafloxacin, trovafloxacin and ciprofloxacin caused no adverse change in conduction, while sparfloxacin, grepafloxacin and moxifloxacin prolonged the duration by 10% or more (Figure 1). The safety of levofloxacin in terms of lack of cardiac adverse events were supported by postmarketing surveillance data. In Japan, only one case of a cardiac adverse event has been reported for levofloxacin, resulting in an incidence of 1 in 8.8 million. The global incidence has only been 8 cases, giving a global incidence of 1 in 1.6 million.

Figure 1. Action potential duration of quinolones at concentration of 100 µM

Figure1

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Guidelines - Should They Be Used in Community-Acquired Pneumonia?

The development of clinical guidelines is likely to continue, and will have a significant impact on how clinicians manage their patients. Professor John G. Bartlett, Johns Hopkins University, Baltimore, MD, USA, presented the Infectious Disease Society of North America (IDSA) guidelines for empiric treatment of community-acquired pneumonia (CAP). In summary, they state that outpatients should receive either a macrolide, fluoroquinolone or doxycycline. Hospitalized patients should receive a beta-lactam plus a macrolide or a fluoroquinolone alone. If a patient requires treatment in an intensive care unit they should receive a beta-lactam plus either a macrolide or a fluoroquinolone.

Professor Lionel Mandell, McMaster University, Hamilton, ON, Canada, reported that advantages associated with use of CAP guidelines include a 30% reduction in length of stay (LOS) and a 50% reduction in cost. Another study found a significant reduction in LOS and mortality for both ward and intensive care patients (p = 0.006, p = 0.016, respectively). However, not everyone is an advocate of guidelines. Professor Ethan Rubinstein, Tel Aviv University School of Medicine, Tel Aviv, Israel, described them as paternalistic, insensitive to individual patients, and thought that cost-reduction was their only benefit. Ongoing development of guidelines will need to overcome these concerns, and further validation will be required to prove their clinical utility.

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Last updated December 21, 2000.