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toumei ../image Special Interview
Levofloxacin and Its Effective Use against RTI-Related Resistant Pathogens

Clyde Thornsberry

An interview with
Clyde Thornsberry
, PhD
Chief Scientific Advisor
MRL Pharnaceutical Services
Brentwood, TN
USA


toumei ../image  A ntibacterial resistance has become a significant problem worldwide, and one that is continuing to increase. With the already high degree of morbidity and mortality associated with respiratory tract infections (RTIs), resistance presents the clinician with a difficult therapeutic problem. Unfortunately, such RTI-related resistant pathogens are becoming common. Penicillin-resistant Streptococcus pneumoniae has been identified in all corners of the globe, and macrolide and beta-lactam resistance are also huge problems. Faced with this situation, it is imperative that agents are available for the effective treatment of these infections.

Levofloxacin, a new "respiratory" fluoroquinolone, is one such agent. It not only has excellent activity against penicillin-resistant organisms, but it also maintains efficacy against beta-lactamase-producing pathogens as well as those resistant to macrolides. It also offers effective treatment for many of the atypical respiratory tract pathogens including Legionella. It is therefore very important that the excellent activity of levofloxacin is maintained by judicious clinical use. A ground-breaking surveillance study has been performed by Dr. Clyde Thornsberry, Chief Scientific Advisor, MRL Pharnaceutical Services, Brentwood, USA, who has been monitoring resistance patterns to respiratory pathogens throughout the United States. Results from his study confirm that while resistance to other agents is increasing, levofloxacin has maintained its activity, providing the clinician with an extremely effective agent for treating these serious infections. Results from this study are outlined by Dr. Thornsberry, who translated this data into important clinical guidelines for the optimal treatment of RTI-related resistant pathogens.

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Questions

Q1. Resistance to commonly used antimicrobials for the treatment of respiratory tract infections (RTIs) is increasing and new compounds for effective therapy are urgently needed. When did this resistance begin in the respiratory setting and how much of a clinical problem is it today?

Q2. Could you discuss any international and regional differences in RTI-resistance patterns?

Q3. The rapid increase in RTI-resistant pathogens has led to the urgent need for newer, more effective antibiotics. One such compound is the fluoroquinolone, levofloxacin. What is the antibacterial activity of levofloxacin, and how does this relate to the pathogens commonly encountered in RTIs?

Q4. Is resistance to fluoroquinolones a problem in the respiratory setting?

Q5. Are there any reports of significant resistance to levofloxacin?

Q6. When fluoroquinolone resistance does occur, what are the possible mechanisms by which it develops?

Q7. Could you comment on the pharmacokinetic and pharmacodynamic features of levofloxacin in regard to RTIs?

Q8. How do these pharmacologic characteristics of levofloxacin translate into the clinical setting?

Q9. Could you compare levofloxacins activity in this setting with other agents including other fluoroquinolones?

Q10. What is the activity of levofloxacin against atypical pathogens?

Q11. You have performed a surveillance study of antimicrobial resistance. Could you give an overview of this study and its rationale?

Q12. What sensitivity testing method did you use?

Q13. What were the results from your study in regard to S. pneumoniae?

Q14. What were your results regarding Moraxella- and Haemophilus-resistance?

Q15. What effect do you see your study results having on clinical decision-making for the treatment of RTIs?

Q16. What advantages does levofloxacin have over other agents?

Q17. What areas of future research do you believe would be useful to undertake in this area?

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Answers

Q1. Resistance to commonly used antimicrobials for the treatment of respiratory tract infections (RTIs) is increasing and new compounds for effective therapy are urgently needed. When did this resistance begin in the respiratory setting and how much of a clinical problem is it today?

A1. In the respiratory setting, the most important problem is that of penicillin-resistant Streptococcus pneumoniae. This problem essentially started in the '60s when the first reports came out of Australia (1). In the succeeding years, occasional reports of elevated minimum inhibitory concentrations (MICs) or reduced susceptibility of S. pneumoniae to penicillin were made, but the first real clinical problems occurred with South African outbreaks (2). Fortunately, these were quite isolated episodes and the rest of the world did not see penicillin resistance at that time. This first changed in Spain where clinicians and researchers began to hear about and see elevated resistance of pneumococci to penicillin (3). During the '80s, there was not a great deal of concern, although even then, US studies showed a 4-5% pneumococci penicillin-resistance rate (4). The rate stayed relatively stable until the early '90s when it dramatically increased up to 20% and has continued to increase during the rest of the '90s (5). This problem is of even more significance when it is taken in consideration of the fact that penicillin-resistant S. pneumoniae is also much more likely to be resistant to other common agents; for instance, the macrolides. The exception to this problem of multiple-resistant pneumococci is that there is no association between penicillin resistance and fluoroquinolone resistance as there is for the beta-lactams, macrolides, clindamycin, tetracyclines and sulphonamides (5).

The other major concern regarding resistance is that of Haemophilus influenzae and Moraxella catarrhalis, where the physician needs to be concerned about beta-lactamase production. With this ever increasing problem of enhanced resistance to commonly used agents, such as beta-lactams and macrolides, it is extremely important that we develop drugs that are not related to any of these resistances. It is in this situation that fluoroquinolones have an important role to play.

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Q2. Could you discuss any international and regional differences in RTI-resistance patterns?

A2. There are marked regional differences across the United States (5). Without a doubt, the Southeast region has more penicillin-resistant S. pneumoniae than other areas. The reason for this is not clear although it does not appear to be due to different prescribing patterns. However, while there are differences within the US, the most striking differences are worldwide (Thornsberry et al., unpublished data). Recent studies looking at penicillin resistance in Germany demonstrate an incidence of approximately 8%, while immediately "next door" in France the rate is a vastly greater 67%. These huge differences between countries in terms of resistant rates are not just apparent for penicillin, but also other antimicrobials. For example, clarithromycin resistance in China is a staggering 74% but in England it is only about 7%, and there are also vast differences in sulfonamide-resistance rates worldwide (30% in China and 1% in the UK). The amount of beta-lactamase-producing organisms present in the community also varies enormously from country to country. In Germany, the amount of beta-lactamase positive H. influenzae is about 6% compared to a much greater rate of 33-35% in the US. If the history of resistant H. influenzae is followed, it is apparent that beta-lactamase production usually increase in steps and I think at the moment it is on a plateau. However, I also believe it is likely that there could be another increase in this resistance over the near future.

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Q3. The rapid increase in RTI-resistant pathogens has led to the urgent need for newer, more effective antibiotics. One such compound is the fluoroquinolone, levofloxacin. What is the antibacterial activity of levofloxacin, and how does this relate to the pathogens commonly encountered in RTIs?

A3. The principal pathogen associated with RTIs remains S. pneumoniae (6-8), and essentially all of these organisms are susceptible to levofloxacin, with only very rare exceptions (5). The second most commonly encountered RTI pathogen is H. influenzae, with M. catarrhalis a more distant third. H. influenzae and M. catarrhalis are all susceptible to fluoroquinolones such as levofloxacin, and there are no resistant strains (5). Levofloxacin has excellent antibacterial activity against not only these principal pathogens, but is also extremely effective against more atypical pathogens such as Legionella pneumophila and Chlamydia pneumoniae.

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Q4. Is resistance to fluoroquinolones a problem in the respiratory setting?

A4. Fluoroquinolones were first used for Gram-negative infections for which they possessed extremely good activity (6, 9). While there are pockets of fluoroquinolone resistance among these species, in general, Gram-negative organisms remain very susceptible to fluoroquinolones. There has been talk about the problem of resistance developing in Escherichia coli but, in fact, the amount of clinical resistance in these bacteria is very rare. It is important to differentiate between decreased susceptibility versus increased resistance. For instance, when an MIC changes from 0.004 µg/ml becoming 0.025 µg/ml, there has obviously been a decrease in the susceptibility of the organism. However, in this situation the organism is still very susceptible clinically and is not resistant. The exception to this is Pseudomonas aeruginosa. Present reports indicate that approximately 20% of P. aeruginosa are resistant to fluoroquinolones in the US. However, when interpreting data, it is important to check that when an institution reports a high resistance rate, that it is not the same strains that have been horizontally transmitted within the institution. With Gram-positives, the amount of fluoroquinolone resistance seen in Staphylococcus aureus depends on the amount of methicillin-resistant S. aureus (MRSA) present. For example, in Gram-positive organisms, if there is an MRSA, the organism is also more likely to have a degree of fluoroquinolone resistance. In the US, the amount of MRSA is reported to be approximately 25%, with the amount of fluoroquinolone resistance about the same. In contrast, there is very little fluoroquinolone resistance noted in methicillin-susceptible S. aureus (MSSA). Fluoroquinolone resistance in streptococci is also not a major problem, with data showing no change in resistance of S. pneumoniae to ciprofloxacin during the 10-year period from 1988 to 1998 (10).

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Q5. Are there any reports of significant resistance to levofloxacin?

A5. The short answer to this question is "No". One of the most important findings we have made in recent years is that if you have a S. pneumoniae penicillin-resistant organism, it is also most probably resistant to multiple agents apart from the fluoroquinolones and vancomycin (Table 1).

Table 1. Association of penicillin resistance in Streptococcus pneumoniae with other selected antimicrobial agents
Table_1

We have shown that if an organism has a penicillin MIC of 2 µg/ml, then susceptibility to all other beta-lactams, macrolides, sulphonamides and clindamycin will be extremely low. However, there is absolutely no correlation between penicillin resistance of pneumococci and resistance to levofloxacin. This is the primary reason for the rapid increase in use of fluoroquinolones in the management of RTIs. Three to four years previously, it was generally believed that fluoroquinolones should not be first-choice agents for community-acquired pneumonia. Now, with the vastly superior bacterial spectrum associated with the newer agents such as levofloxacin, coupled with their efficacy against penicillin-resistant S. pneumoniae, they are widely seen as favored agents. In fact, in the US, the American Thoracic Society's most recent recommendation for hospitalized patients with community-acquired pneumonia (CAP) includes fluoroquinolones. The Infectious Disease Society of America and the Medical Letter also recommend fluoroquinolones for treating hospitalized CAP patients.

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Q6. When fluoroquinolone resistance does occur, what are the possible mechanisms by which it develops?

A6. High level resistance to fluoroquinolones can occur in S. pneumoniae following a DNA gyrase mutation and topoisomerase IV mutation (11-13). Since two mechanisms are involved, the development of high level resistance is less likely with these agents. The incidence of fluoroquinolone-resistant strains could possibly increase in an institution through selective pressure in conjunction with horizontal transfer. Another mechanism is via efflux, although I do not think this will be a major issue at this time.

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Q7. Could you comment on the pharmacokinetic and pharmacodynamic features of levofloxacin in regard to RTIs?

A7. An extremely important advantage levofloxacin has in this setting is that it is the purified isomer of the racemic parent compound, ofloxacin. Therefore, all of the pharmacologic data accumulated over many years for ofloxacin is of use in evaluating levofloxacin. We already know that ofloxacin has excellent pharmacokinetic, pharmacodynamic, and safety characteristics, and these are easily transferable to levofloxacin. Therefore, levofloxacin provides the physician with an agent possessing the pharmacokinetic and pharmacodynamic profile of ofloxacin, but coupled with enhanced activity. Levofloxacin achieves very high levels in the respiratory tissues, being almost 100% bioavailable following oral administration. This is a significant advantage in terms of treating RTIs because the excellent distribution in tissues, bronchial secretions and sputum allows levofloxacin to achieve levels that are considerably higher than the MIC90s of most of the causative RTI pathogens. There are reports that the peak lung levels achieved by levofloxacin may be somewhere around 10-12 µg/ml which is considerably higher than MIC90s of the pathogens (14, 15). Levofloxacin achieves levels in macrophages which are much higher than in serum and this has considerable clinical significance, allowing it to provide effective treatment of intracellular pathogens. Levofloxacin has a long half-life with a significant postantibiotic effect (PAE), allowing extremely effective once-daily dosing schedules to be employed. It does not interact with other agents which an elderly patient with a serious RTI is likely to be taking such as theophylline. It is excreted in the urine and can be given both orally or parenterally allowing easy switch between both administration forms.

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Q8. How do these pharmacologic characteristics of levofloxacin translate into the clinical setting?

A8. Levofloxacin has good activity against all of the strains causing RTIs, with good in vitro results and even better in vivo results expected because of the exceedingly high tissue levels levofloxacin achieves in respiratory tissue and fluid. This is supported by results from a large, randomized clinical trial published recently by Prof. T.M. File evaluating levofloxacin for the treatment of CAP, compared to cefuroxime and/or ceftriaxone (6). When treating these community-acquired infections, it is difficult for most physicians to get immediate laboratory data to base their treatment on and therapy has to be prescribed empirically. In this situation, levofloxacin is an excellent choice because, even if the causative pathogen is a penicillin-resistant S. pneumoniae, it is covered by levofloxacin (6-8). In addition, levofloxacin has the advantages of allowing the clinician to treat the patient with either intravenous (IV) or oral therapy. Switching from IV to an effective oral regimen as soon as possible is important for discharging hospitalized patients. Of course this offers significant financial savings as well.

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Q9. Could you compare levofloxacin's activity in this setting with other agents including other fluoroquinolones?

A9. Levofloxacin has expanded activity against most of the Gram-positives, particularly S. pneumoniae, compared to earlier fluoroquinolones. This action against S. pneumoniae has become of even more importance because of the rise in resistance. When looking at MICs of the fluoroquinolones, a hierarchy of activity can be built up starting with ofloxacin and ciprofloxacin, and increasing to levofloxacin. Although some of the other newer fluoroquinolones may have stronger in vitro antibacterial activity due to differences in pharmacokinetics and tolerability profiles, levofloxacin possesses many additional advantages over these agents. The pharmacokinetic features of levofloxacin are exceptional (Figure 1).

Figure 1. Concentrations of levofloxacin in patients undergoing fibre-optic bronchoscopy following a single oral 500 mg dose.
Figure_1

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Q10. What is the activity of levofloxacin against atypical pathogens?

A10. Published data clearly indicates that levofloxacin has excellent activity against atypical pathogens including Mycoplasma, Legionella and Chlamydia (6-8, 11-13). These pathogens are all becoming recognized as being of increasing importance in RTIs than previously thought. In the past, erythromycin has tended to be used in this situation, but this is changing with many institutions in the US now preferring to use a fluoroquinolone such as levofloxacin for treating Legionella infections (6).

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Q11. You have performed a surveillance study of antimicrobial resistance. Could you give an overview of this study and its rationale?

A11. Our aim when doing this Tracking Resistance in the United States Today study (TRUST) was to gain data on what the rates of resistance were in the US for S. pneumoniae, H. influenzae and M. catarrhalis (5). Four hundred and thirty-four healthcare institutions participated in the study. We set out to enroll as many institutions as possible and the study was designed to principally investigate S. pneumoniae and test the organism against a range of agents including levofloxacin; a second-generation cephalosporin, cefuroxime; a third-generation parenteral cephalosporin, ceftriaxone; and a macrolide, clarithromycin. MICs were performed on all organisms with these drugs to get true resistance rates in the US. At the completion of the study we had 11,368 isolates from 45 of 48 states. We tested over 9,000 S. pneumoniae, 1,500 H. influenzae and 600 M. catarrhalis to determine MICs which were placed in categories of susceptibility based on the recommendations of the US National Committee for Clinical Laboratory Standards (NCCLS).

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Q12. What sensitivity testing method did you use?

A12. All institutions carried out MIC determinations using the E-test method which is performed in a manner similar to a disk-diffusion test. When designing this study, we felt it best to get the laboratories involved to carry out the testing themselves, so we provided them with E-test material. A number of strains arbitrarily selected were sent to us and we tested them using both the E-test and microbroth dilution. E-test is a very well accepted method for determining S. pneumoniae and approved by the FDA. However, there is one area of concern when assessing E-test results in regard to macrolide sensitivity. According to the E-test methodology, the test is performed on the surface of an agar plate and therefore CO2 is present which affects pH on the agar surface. Because macrolides are very pH dependent, this could potentially affect results. However, when looking at the amount of resistance to clarithromycin as a ratio of susceptible to resistant S. pneumoniae, it did not affect the clinical susceptibility results since any changes were far away from the break points. One place in the study where it probably did change results was in regard to clarithromycin and H. influenzae. In this instance, the numbers we got for % resistant are probably elevated to what is actually true. When we did the second part of the study (TRUST II), we performed all assessments ourselves, testing all samples by broth microdilution as recommended by NCCLS with rigidly quality-control so results were not affected by environmental conditions.

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Q13. What were the results from your study in regard to S. pneumoniae?

A13. We found about 20% of more than 9,000 strains of S. pneumoniae were intermediate in their susceptibility to penicillin as defined by MICs of 0.1-1 µg/ml (5). About 14% had high-level penicillin resistance defined as MIC gte 2 µg/ml. This latter finding was alarming because earlier studies had reported high-level resistance to be practically zero before the '90s, increasing to 2.5% in the early '90s and in 1995 the incidence of high-level resistance was about 6% (5, 12) (Thornsberry, unpublished data) (Figure 2).

Figure 2. Increasing penicillin resistance for Streptococcus pneumoniae in the 1990s.
Figure_2

Clearly the biggest increase is in the incidence of high-level penicillin resistance. This is of even more importance when you consider that it is high-level resistant strains which tend to be associated with multiple resistance to other drugs commonly used to treat upper RTIs, except fluoroquinolones and vancomycin. Therefore, combination intermediate and high-level penicillin resistance was demonstrated to be present in approximately a third of the S. pneumoniae. In order to understand the significance of resistance in S. pneumoniae, it is necessary to assess this according to the following: penicillin-resistant, penicillin-intermediate and penicillin-sensitive organisms (Table 2) (5).

Table 2. Susceptibility of selected respiratory tract pathogens to levofloxacin and clarithromycin based on resistance to penicillin.
Table_2

If penicillin-intermediate-resistant strains are looked at along with highly resistant strains, it can provide deceiving results. I believe that in a few years due to this large group of penicillin-intermediate strains, the highly resistant rates will increase even further to 38-40%. The results from the surveillance study also revealed a significant 4-5% increase in the incidence of macrolide-resistance.

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Q14. What were your results regarding Moraxella- and Haemophilus-resistance?

A14. Of the 1,558 H. influenzae isolates tested, 33.4% produced beta-lactamase and 32.5% were resistant to ampicillin (Table 3) (5).

Table 3. The susceptibility of Haemophilus influenzae isolates to selected antimicrobial agents.
Table_3

The resistance rates to the other agents (amoxicillin-clavulanate, cefuroxime, ceftriaxone) were relatively low. The overall activity of clarithromycin was: 58.1% susceptible, 32.4% intermediate and 9.5% resistant (may have been affected by the CO2 in the test method). All isolates of H. influenzae were susceptible to levofloxacin with MICs of < 2 µg/ml and an MIC90 of 0.064 µg/ml. Nearly all M. catarrhalis were resistant to ampicillin with 93% of the M. catarrhalis producing beta-lactamase. All M. catarrhalis isolates were susceptible to levofloxacin (Table 4) (5).

Table 4. The susceptibility of Moraxella catarrhalis isolates to selected antimicrobial agents.
Table_4

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Q15. What effect do you see your study results having on clinical decision-making for the treatment of RTIs?

A15. The predominant use of fluoroquinolones is in the outpatient setting because of their excellent activity when given orally. Most clinicians in this setting do not have access to immediate microbiological assessment, and therefore, empirical treatment is initiated (6-8). The decision of which antimicrobial to use then needs to be based upon the likely pathogen and whether it is a possible resistant organism. Therefore, it is important that the clinician has access to epidemiological data to help him in choosing the optimal agent. This surveillance data on resistance patterns will aid in making a decision on the likelihood of treating patients with penicillin-resistant S. pneumoniae. In this regard, the critical finding of our study is the sharp increase in pneumococci with high-level resistance, since these organisms are also more likely to be resistant to other commonly used agents such as macrolides and beta-lactams. In sharp contrast, we found no association between penicillin resistance and fluoroquinolone resistance in S. pneumoniae and because fluoroquinolones are oral agents with a wide spectrum of activity, they become the therapy of choice in this situation.

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Q16. What advantages does levofloxacin have over other agents?

A16. I believe that levofloxacin has several very important advantages over other fluoroquinolones as well as other commonly used RTI antimicrobials. First, it is an agent which has been developed based upon the history of its parent compound, ofloxacin. Therefore, we already know a great deal about its clinical features and safety. The safety issue is very important, as levofloxacin, like ofloxacin, is known to have a very low rate of adverse events and to be very well tolerated by the vast majority of patients. We know that levofloxacin has far less potential as a photosensitiser than many other fluoroquinolones, and when treating outpatients, this is an especially important benefit. Further advantages compared to non-fluoroquinolone agents include: its excellent tissue penetration and distribution; high levels in macrophages, which is a definite advantage over beta-lactams; its wide spectrum of activity with a low MIC against most organisms including atypicals; and its proven effectiveness against L. pneumophila. It is therefore, a useful agent for therapy of respiratory infections.

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Q17. What areas of future research do you believe would be useful to undertake in this area?

A17. I believe that undertaking this surveillance study, even before levofloxacin was approved, sets a standard which will have to be followed in the future for all drugs. It is important that we monitor the development of resistance prior to a drug being used, and continue surveillance through its increasing exposure in the community. Therefore, I think it is very important to continue this surveillance study. Another area which should be looked at concerns what is happening among the Gram-negative rods, using very standardized studies to see any change in MICs. We also need to look at epidemiology to investigate issues such as horizontal transfer and genetic typing of resistant strains.

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References

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  11. Hooper DC, Wolfson JS, eds. Quinolone Antimicrobial Agents 2nd. Washington DC: American Society for Microbiology, 1993.
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  15. Smith RP, Baltch AL, Franke M, Hioe W, Ritz W, Michelsen P. Effect of levofloxacin, erythromycin or rifampicin pretreatment on growth of Legionella pneumophila in human monocytes. J Antimicrob Chemother 1997; 40: 673-8.

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