Highlights of the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy
San Diego, 24-27 September, 1998
The increasing incidence of resistance among important respiratory tract pathogens was one of the most topical issues at the 38th ICAAC, with researchers from around the world monitoring this potentially catastrophic problem. With respiratory tract infections (RTIs) the most common of all clinical problems to be managed by physicians, it is imperative that effective treatment continue to be available. RTIs are associated with a huge cost in terms of both morbidity and mortality, with this translating into a significant burden upon healthcare services. It is in this setting that levofloxacin, one of the newest fluoroquinolones, has shown itself to have a potentially pivotal role. Levofloxacin is a broad spectrum antibacterial fluoroquinolone, being the l-isomer of the racemic ofloxacin. It has a wide range of antibacterial activity against both Gram-positive and Gram-negative organisms. Against Gram-positive pathogens, it is active against staphylococci (including MRSA) and streptococcal species, and demonstrates greater bactericidal activity than the earlier formulations of fluoroquinolones, for example, ciprofloxacin.
LEVOFLOXACIN - EXCELLENT PHARMACOLOGIC FEATURES FOR TREATING RTIs
Data presented at a session on fluoroquinolone resistance confirmed the exceptional pharmacologic characteristics which levofloxacin possesses. Dr. David C. Hooper, Massachusetts General Hospital, Boston, USA, drew attention to the fact that newer fluoroquinolones such as levofloxacin, provide 24 hr AUC/MIC values that easily exceed necessary values for Streptococcus pneumoniae. Pharmacokinetic/pharmacodynamic parameters for the quinolones show the need to no longer look simply at MIC values, but to assess AUC/MIC levels. In addition, the new quinolones have significant postantibiotic effects (PAE) against pneumococcus.
These findings were amplified by a report from Dr. Raymond P. Smith et al., Stratton VA Medical Center, Albany, USA, who measured the PAE of levofloxacin and four other antibiotics (azithromycin, ciprofloxacin, doxycycline and erythromycin) against Legionella pneumophila using both the Craig and Gudmundsson method (CG) as well as a mathematical modelling technique (Q PAE). Results confirmed that for slow-growing organisms such as L. pneumophila the Q PAE duration has less intra-assay variation than the CG method and is therefore more reproducible. For L. pneumophila L-1033, the Q PAE duration clearly demonstrated a PAE for levofloxacin, ciprofloxacin and azithromycin but not for erythromycin and doxycycline. The Q PAE demonstrated that PAE is dose dependent for levofloxacin and ciprofloxacin at 5 x, and 10 x the MIC and for azithromycin at 10 x MIC. No PAE could be detected at 1 x MIC for these agents. In fact the PAE at 10 x MIC was the longest for levofloxacin (Table 1).
Table 1. Results of a single experiment in which samples were taken every 1 to 2 hours for 24 hours following drug removal (hour 3)a to assess effect of levofloxacin on Legionella pneumophila L-1033
a For L-1033, all controls, all assays, normal linear growth (hours 3-9) is 0.166 log.
b Counts at hours 3, 5, 6, 7, 8, 9, 24.
CGT log = Craig and Gudmundsson method of assessing PAE.
QT log = Mathematical modelling method of assessing PAE.
The long PAE associated with levofloxacin means that it is more likely than the other agents to maintain efficacy against slow-growing, intracellular pathogens such as Legionella, which is seen as an important atypical pathogen associated with significant morbidity and mortality.
INCREASED RESISTANCE TO MACROLIDES CONFIRMED
An important study which followed the resistance of S. pneumoniae against clarithromycin, penicillin and levofloxacin in the US during the 1996-97 respiratory season was reported by Drs. Yolanda Mauriz, Clyde Thornsberry, and James Kahn, MRL Pharmaceutical Services and Ortho-McNeil Pharmaceutical, USA. This study noted that since the majority of prescriptions for RTIs are written in the outpatient setting, few laboratories test for susceptibility to macrolides. The TRUST study examined 9,190 isolates of S. pneumoniae using E test and NCCLS breakpoints. They reported that the resistance rate to one of the macrolides, clarithromycin, was 18.2%, which was even higher than the rate of high level penicillin resistance (13.7%) (Figure 1).
Figure 1. Tracking the changing U.S. resistance patterns of S. pneumoniae
Source: Tracking Resistance in the United States Today, Ortho-McNeil Pharmaceutical, Inc. and Daiichi Pharmaceutical Co. Ltd., 1998
These rates had both increased from values recorded in previous years. It was also important to note that although there were regional differences in resistance rates, in no part of the US did resistance to macrolides or penicillins drop below 10%. In stark contrast, the resistance to levofloxacin was exceptionally low, ranging from 0.4 to 1.1%. These results confirmed that increasing penicillin resistance in pneumococcus is linked to increasing macrolide resistance, but not to levofloxacin resistance. These results are of great significance given the fact that, in the US, macrolides are among the most commonly prescribed agents for RTIs. In the light of these results, this may need to be reconsidered, with fluoroquinolones such as levofloxacin showing they possess significant advantages in treating these infections.
Adding to this data were results from an international surveillance study which monitored resistance among respiratory tract pathogens in Asia and Europe over the 1997-98 period. Dr. D.R. Diakun et al., MRL Pharmaceutical Services, USA, noted that because resistance among S. pneumoniae can develop quickly, large regional and national differences can be seen, necessitating international surveillance. This study monitored resistance among S. pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in China, Japan, France, Italy, Germany, Spain and the United Kingdom. Testing was performed at a central laboratory using broth microdilution. Among S. pneumoniae, susceptibility was 67% compared to 99.7% for levofloxacin, while only 66% were susceptible to azithromycin and clarithromycin, and 65.8% were susceptible to trimethoprim-sulfamethoxazole (TMP-SMX). Again it was confirmed that as resistance to penicillin increased, so too did the resistance to -lactams. Dramatic differences in resistance were detected between countries for -lactams, macrolides and TMP-SMX. For example, the prevalence of -lactamase producing H. influenzae ranged from 6% in China and Germany to 32% in Spain (Table 2).
Table 2. Geographic distribution of penicillin-nonsusceptible (NS) strains (resistant plus intermediate) and -lactamase production
a Only one M. catarrhalis strain was isolated from China.
All isolates of H. influenzae and M. catarrhalis were susceptible to levofloxacin. The authors stressed the need for ongoing surveillance of these worrying trends to ensure the optimal management of patients with RTIs, and in order to detect any changes in the status of the highly active agents such as levofloxacin.
SUSCEPTIBILITY TO LEVOFLOXACIN REMAINS HIGH
Results from a UK multicentre study of levofloxacin susceptibility among respiratory tract pathogens isolated from patients in both the community and hospital setting were reported by Dr. R.G. Masterton et al., Western General Hospital, Edinburgh, UK. This study noted that despite the continued evolution of new antibiotics, the development of resistance among pathogens remains a problem, making effective treatment of these common infections more difficult. This study was undertaken to provide a current evaluation of the contribution which levofloxacin can make against RTIs and the most common pathogens causing these infections. The results demonstrated that currently in the UK, a wide range of respiratory tract pathogens exhibit high levels of susceptibility to levofloxacin. Amongst organisms causing community-acquired pneumonia the overall susceptibility of isolates to levofloxcain, including cultures of MRSA, was 97.6%.
The in vitro and in vivo activity of ciprofloxacin, levofloxacin and vancomycin against macrolide-resistant, penicillin-resistant S. pneumoniae (penR-SP) was tested in a study performed by Dr. M.S. Rouse et al., Mayo Clinic, Rochester, USA. This paper again highlighted the problem facing many clinicians of a rapid and significant increase in macrolide resistance among clinical isolates of penR-SP. The MIC90 of 27 clinical isolates of penR-SP was tested, using an experimental model of pneumonia in immunocompetent mice. Results outlined in Table 3 confirm that in this experimental model of macrolide resistant, penR-SP, levofloxacin or vancomycin were more effective (p < 0.05) than ciprofloxacin.
Table 3. Susceptibility testing of penicillin-resistant Streptococcus pneumoniae to four antimicrobials
a MIC90 of 27 clinical isolates of penicillin-resistant pneumococci.
In many institutions, it is important that vancomycin is used as sparingly as possible to maintain its efficacy. Therefore, these results clearly indicate an important role for levofloxacin in helping to treat these multidrug-resistant pathogens which unfortunately are being seen more often.
OVERCOMING THE DEVELOPMENT OF RESISTANCE
Possible mechanisms to overcome the development of resistance were also featured in a number of presentations at the meeting. Among these, one important study, presented by Dr. J.R. Aeschlimann et al., Detroit Receiving Hospital, Detroit, USA, investigated the impact of NorA efflux pump inhibition on the activity of levofloxacin, ciprofloxacin and norfloxacin against Staphylococcus. aureus. It has been previously documented that the NorA efflux pump is present in wild type strains of S. aureus and enhanced expression of this gene is one possible mechanism leading to the development of fluoroquinolone resistance. Therefore, by inhibiting NorA, intracellular levels of the fluoroquinolones can be increased, leading to greater activity. This is particularly so since it is now well recognized that fluoroquinolone activity depends on the ratio of the peak: MIC or area under the concentration-time curve (AUC): MIC, and NorA inhibition could lead to improved pharmacodynamic characteristics in this regard. Omeprazole, a NorA inhibitor, was used in a study assessing the development of resistance to three fluoroquinolones, levofloxacin, ciprofloxacin and norfloxacin. Results led the researchers to conclude that levofloxacin had the greatest activity against both strains of S. aureus and NorA did not affect its activity (Table 4).
Table 4. Effect of levofloxacin, ciprofloxacin and norfloxacin ± omeprazole on bacterial inoculum
a Both strains are fluoroquinolone susceptible.
The alterations in activity related to NorA and its inhibition correlated strongly with known pharmacodynamic predictors of fluoroquinolone activity. This means that of the three fluoroquinolones tested, levofloxacin was the most active and the least likely to have resistance develop against it, which is certainly a very potent advantage in these times of heightened concern over resistance worldwide.