Highlights from the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy
Toronto, Canada, September 28-October 1, 1997
The Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meetings continue to be one of the most influential and important congresses occurring each year in the field of infectious disease and chemotherapy. The 37th ICAAC, held from September 28-October 1, 1997, in Toronto, attracted more than 15,000 scientists from around the world to take part in an extensive scientific program which included symposia, slide sessions, state of the art minilectures, an astounding array of poster sessions and more. One of the newest antimicrobials carving a significant niche for itself is the fluoroquinolone levofloxacin, which was shown to be extremely effective in a wide range of infections. With excellent pharmacokinetic and pharmacodynamic features, allowing once-daily oral administration, levofloxacin will become an important adjunct to the treatment of many infections. Of special note is the role levofloxacin has in the treatment of respiratory tract infections (RTI) where it was demonstrated to be very effective for community-acquired pneumonia (CAP) and acute exacerbations of chronic bronchitis (AECB).
Levofloxacin - Superior Treatment for ABECB
Chronic obstructive pulmonary disease (COPD) causes a significant and increasing amount of morbidity and mortality throughout the world. Included among these syndrome are chronic bronchitis and AECB, the principal pathogens of which are Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae. Previously these infections have been treated by a number of antimicrobials, but in the last two decades significant antibiotic resistance has emerged among these principal bacteria. Therefore, there has become an urgent need for new effective strategies to treat AECB and levofloxacin was proven to be such a strategy in results.
A comparative study presented by Dr. Shah, Germany, confirmed that once-daily levofloxacin was as effective as cefuroxime axetil twice-daily in the treatment of AECB. Dr. Shah compared the safety and efficacy of levofloxacin 250 or 500 mg once-daily with cefuroxime axetil 250 mg twice-daily. Treatment duration was 7-10 days, with 839 patients enrolled, 832 of whom were evaluable on an intent-to-treat basis. Both doses of levofloxacin achieved a higher clinical success rate than that achieved by cefuroxime axetil (Table 1). In addition the clinical cure rate in patients with more severe disease (peak flow rate <300 ml/min) was higher in levofloxacin than in those patients treated with cefuroxime axetil. Bacteriological eradication rates were also higher for levofloxacin (77% compared to 68% for cefuroxime axetil). Eighty percent of the Gram-negative pathogens 80% were eradicated by levofloxacin compared to 60% for cefuroxime axetil.
Table 1. Clinical success rates
Two other comparative respiratory tract studies assessed levofloxacin first against co-amoxicillin clavulanate (CA) and the second against ceftriaxone/cefuroxime axetil. Results from both studies confirmed the additional advantages provided by levofloxacin.
The first study was an international cooperative effort in which levofloxacin 500 mg once-daily or twice-daily was compared to CA 500/125 mg t.i.d. Clinical response 2-10 days after treatment demonstrated a cure rate of 95.2% for levofloxacin once-daily, 93.8% for the twice-daily schedule and 95.3% for CA t.i.d. Intent-to-treat results are shown in Table 2. Total eradication rates were levofloxacin once-daily 97.8%, levofloxacin twice-daily 100% and CA 97.5%. The researchers concluded that levofloxacin 500 mg once-daily was as effective as the twice-daily regimen, and the thrice-daily dose of CA. Therefore the once-daily dose of levofloxacin offers significant advantages in terms of compliance and cost-effectiveness, making it an effective and safe alternative for the treatment of mild to moderately severe CAP in adults.
Table 2. Clinical response (cure rates) post-therapy
The second study presented by Dr. File, USA, confirmed the excellent efficacy of levofloxacin for CAP. Five hundred and ninety patients were enrolled. Not only were the bacteriological eradication rates superior for levofloxacin, but this translated into a definite clinical superiority, with a 96% clinical success rate at 5-7 days post-therapy for levofloxacin compared to 90% for the ceftriaxone and/or cefuroxime axetil group (95% CI, -10.7 to -1.3) (Figure).
Figure. Clinical and microbiological responses at 5 to 7 days post-therapy in clinically and microbiologically evaluable patients. Clinical success*, sum of cured and improved.
Atypical Pathogens Effectively Treated by Levofloxacin
It is becoming increasingly recognised that atypical pathogens are of increasing importance in the pathogenesis of RTI. It is in this setting that levofloxacin offers further advantages compared to some of its competitors, which often are less active, if at all, against these bacteria. Chlamydia is one such class of atypical pathogens and Dr. Cevenini, Italy, investigated the in vitro activity of levofloxacin against C. trachomatis, C. pneumoniae and C. psittaci. This activity was also compared with that of ofloxacin, minocycline, tetracycline, and doxycycline. The MICs of levofloxacin against chlamydial strains ranged between 0.5 and 1 µg/ml and were higher than those of tetracyclines. The MBC values of levofloxacin were higher than those of minocycline, but equal or lower than those of doxycycline, tetracycline and ofloxacin. MBCs of levofloxacin were the same as the MICs, whereas those of the tetracycline were 2-3 times higher than the MICs confirming that levofloxacin is bactericidal against chlamydial strains in a single growth cycle at a concentration equivalent to the MIC, while the bactericidal activity of tetracyclines is achieved at a concentration about two orders of magnitude higher than the MIC. These findings suggest that levofloxacin has superior activity against these pathogens compared to tetracyclines.
Grave Concern Over Increasing Drug Resistance
The Alexander project is an ongoing international multi-centre study, initiated in 1992 to monitor trends in the antimicrobial susceptibilities of community-acquired lower respiratory tract pathogens. Results from this demonstrate that there is increasing prevalence of ß-lactam-resistant H. influenzae isolates (15.4% in Europe, and 28.4% in USA). Of grave concern is the fact that since 1992, the prevalence of penicillin-resistant has doubled to 12.3% in the USA and 23.9% in Europe. Most participating centres showed a strong correlation between penicillin- and macrolide- resistance among isolates of S. pneumoniae. Greater than 90% of M. catarrhalis isolates in both the USA and Europe now produce ß-lactamase.
One bright spot amid this gloom, was provided by results showing levofloxacin to be very effective against S. pneumoniae isolates. Dr. Ploufe and the Franklin County Pneumonia Study Group demonstrated that levofloxacin has excellent activity in vitro against bacteremic isolates of S. pneumoniae, with 99.2% of 499 isolates having MICs <2 µg/ml (Table 3). Over the period 1991-94, resistance to levofloxacin has not increased, consistent with observations of minimal change in levofloxacin's MICs with serial passage (Table 4). Dr. Ploufe concluded that levofloxacin has excellent activity in vitro against bacteremic isolates of S. pneumoniae, including isolates not susceptible to penicillin.
Table 3. Correlation of Levofloxacin Broth Dilution Minimum Inhibitory Concentration (MIC) Value with Disk Diffusion Zone Diameter
Table 4. Number (%) of Bacteremic Isolates of Streptococcus pneumoniae by Levofloxacin Minimum Inhibitory Concentration (MIC) and Year