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A Comparison of Clinical Outcomes Using Levofloxacin versus ß-lactams and Macrolides in Respiratory Tract Infections

Raymond P. Smith

An interview with
Raymond P. Smith
, MD
Infectious Disease Section
Stratton VA Medical Center
Albany, NY
USA


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 R espiratory tract infections (RTIs) are one of the most common problems faced by physicians. As such, they place a huge burden upon health systems worldwide, and are associated with massive financial costs for both the individual and society. It is therefore extremely important that we have antibacterial agents which are effective against these ubiquitous infections. Levofloxacin, one of the newest fluoroquinolones, is such an agent. It has an excellent antibacterial spectrum, being effective against Gram-negative and Gram-positive organisms including penicillin-resistant Streptococcus pneumoniae, as well as atypical organisms. It penetrates into the respiratory tissues extremely well and, due to its excellent pharmacokinetic and pharmacodynamic characteristics, is effective when given in a once-daily dosage. To compare the role of levofloxacin against other classes of antimicrobials commonly used for RTIs, Penetration interviewed Dr. Raymond P. Smith, Infectious Disease Section, Stratton VA Medical Center, Albany, USA, who has performed an in vitro study investigating levofloxacin versus macrolides and rifampicin. Using results from this study, as well as reviewing all of the latest relevant literature, Dr. Smith was able to provide a comprehensive overview outlining the indications for these agents. He confirmed that levofloxacin is a drug of choice for treating many of these infections, and has a particularly important role when penicillin-resistant S. pneumoniae is the causative pathogen.

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Questions

Q1. What is the antibacterial activity of levofloxacin and how does this relate to the pathogens commonly encountered in respiratory tract infections (RTIs)?

Q2. Could you comment on the pharmacological features of levofloxacin in regard to RTIs?

Q3. What advantages do these pharmacologic features of levofloxacin provide over other agents in the treatment of RTIs?

Q4. Could you discuss the role of levofloxacin in the treatment of specific upper respiratory tract infections (URTIs), and compare this to other commonly used agents in this setting?

Q5. What role do you see levofloxacin playing in lower respiratory tract infections (LRTIs) and again contrast this to other agents?

Q6. In which patients would you use oral versus IV therapy, and could you comment on the use of sequential therapy using levofloxacin (IV switching to oral) and the advantages this offers the physician in the treatment of RTIs?

Q7. It has recently been reported that macrolides are not an ideal empirical therapy for CAP. Would you agree with this?

Q8. Could you comment on the activity of levofloxacin against biofilm-forming bacteria such as Pseudomonas aeruginosa, and how this compares with other antibacterials?

Q9. The atypical pathogens are often being cited as becoming more of a clinical problem in RTIs. Could you comment on the use of levofloxacin against these pathogens?

Q10. What is the activity of levofloxacin against Legionella species and could you compare this with other agents?

Q11. You performed a study investigating the effect of levofloxacin, erythromycin and rifampicin pretreatment on growth of L. pneumophila in human monocytes. Could you describe your study and its aim?

Q12. What were the results of your study?

Q13. Do you see any situations in which combination therapy using levofloxacin plus another agent may be indicated?

Q14. How does the safety and tolerability of levofloxacin compare to other agents?

Q15. In some chronic RTI, longer treatment schedules are required. Could you discuss the safety of levofloxacin in this situation?

Q16. Does levofloxacin offer specific advantages to the physician and patient over other agents in the treatment of immunocompromized patients?

Q17. If you were asked to briefly summarize the relative advantages levofloxacin has over other antibiotics in the treatment of RTIs, what would you say?

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Answers

Q1. What is the antibacterial activity of levofloxacin and how does this relate to the pathogens commonly encountered in respiratory tract infections (RTIs)?

A1. Levofloxacin has an outstanding in vitro antibacterial action for all of the most common RTI pathogens. This coupled with the fact that it possesses much improved activity for less common pathogens like Legionella pneumophila make it a highly appropriate agent for treating RTIs. It is also exceptional in that it possesses very good activity against penicillin-resistant Streptococcus pneumoniae, one of the most difficult of all respiratory pathogens faced by clinicians today. The MIC90 (minimum concentration at which 90% of tested strains are inhibited) of levofloxacin against this pathogen has remained between 1.5-2 µg/ml in most studies, and this is well within safe, achievable concentrations of levofloxacin. In contrast, many of the penicillin-resistant S. pneumoniae isolates now show resistance to other commonly used agents (Table 1)(1).

Table 1. Resistance of penicillin-resistant Streptococcus pneumoniae to other antimicrobial agents (total isolates tested-109)
Table_1

In terms of Gram-negative pathogens, it has been repeatedly shown that levofloxacin has outstanding activity. For example, against Haemophilus influenzae, most studies report more than 98% of strains susceptible, with other studies showing 100% susceptibility rates. In addition, levofloxacin has excellent activity against Moraxella catarrhalis.

Levofloxacin also possesses relatively good in vitro activity against Chlamydia pneumoniae with MIC50 and MIC90 values up to 0.5 µg/ml. This is supported by data from a large clinical study which suggests that this in vitro activity translates into good clinical efficacy (2). Levofloxacin is also active against other atypical pathogens including Mycoplasma pneumoniae with MIC90 values of about 0.5 µg/ml. And of course, there are very few agents with better activity than levofloxacin against L. pneumophila.

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Q2. Could you comment on the pharmacological features of levofloxacin in regard to RTIs?

A2. In terms of quantity of drug delivered to the site of infection, levofloxacin is an outstanding drug even among the newer fluoroquinolones. It has extremely high tissue penetration (3, 4) achieving levels even higher than that found in the serum. In addition, for intracellular organisms, as typified by those caused by L. pneumophila, the ability of levofloxacin to penetrate into both phagocytic and epithelial cells appears to be extremely important. It achieves high concentrations in respiratory secretions and lung tissue and has persistent activity in lung tissue. This persistence in activity is probably related to the intracellular concentration of the drug being well above the inhibitory activity necessary for most pathogens at least 12-13 hr after a dose. It has been shown that against S. pneumoniae and Moraxella, levofloxacin both kills rapidly and has a fairly long residual activity. These features are both extremely important and mean that, even if levofloxacin is given once a day, the residual activity in the tissue and serum is high enough to accomplish prolonged inhibition of bacterial growth. The term post-antibiotic effect (PAE) can be used to describe this effect (5). The interesting thing about levofloxacin compared to other fluoroquinolones is that its PAE for the most important RTI pathogen, S. pneumoniae, occurs even at subinhibitory concentrations (6).

The second important pharmacodynamic characteristic associated with levofloxacin is that it possesses dose dependent killing of S. pneumoniae. Therefore, the initial high peak tissue and plasma and respiratory secretion levels may be translated into a very rapid reduction in the bacterial inoculums. This rapidity with which bacterial killing occurs is very important in terms of antimicrobial activity. This is a very important issue in terms of both outcomes, as well as the speed with which a patient can be switched from intravenous (IV) to oral therapy. While some clinicians may be comfortable treating patients with minor RTIs with agents which are not rapidly bactericidal, such as macrolides or beta-lactams, for the seriously ill patient, the rapid bactericidal activity of levofloxacin against all strains needs to be emphasized. This is one reason why the macrolides may not be highly appropriate in seriously ill community-acquired pneumonia (CAP) patients. In addition, in terms of concern about resistance, rapid killing of a high inoculum infection, such as those of the lower respiratory tract, is a very important consideration in terms of the prevention of resistance.

Recent reports by Drusano and Preston demonstrate that when assessing the pharmacologic activity of levofloxacin, it is important to examine the area under concentrationtime curve (AUC). They performed a very elegant study, taking pharmacologic data from over 260 patients and found that AUC data can be used to predict the most appropriate dose schedule for optimal efficacy in seriously ill patients being treated with levofloxacin (7).

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Q3. What advantages do these pharmacologic features of levofloxacin provide over other agents in the treatment of RTIs?

A3. Compared to beta-lactams, the ability to administer levofloxacin as a single dose because of its long plasma half-life (t1/2), its predictable high peak plasma concentrations (Cmax) which can be adjusted up if necessary in the seriously ill patient by giving higher doses, and the persistence of antimicrobial activity are very important pharmacologic considerations. Compliance is a terribly important issue in the adult with an RTI, so if one compares the need to give a single oral dose to the need to give multiple doses either parenterally or orally, you can see this is a tremendous advantage for levofloxacin, both clinically and in respect to cost-effectiveness.

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Q4. Could you discuss the role of levofloxacin in the treatment of specific upper respiratory tract infections (URTIs), and compare this to other commonly used agents in this setting?

A4. A large study, recently published by Sydnor (8), reported excellent results using levofloxacin in the management of 330 patients with acute maxillary sinusitis, 300 of whom had antral aspirates or sinus punctures to identify the pathogen. The most common organisms identified were S. pneumoniae, H. influenzae, Staphylococcus aureus and Moraxella. Fifty-eight percent achieved a favorable clinical outcome with both clinical and microbiological cure, and another 30% had clinical improvement without obvious bacterial eradication. The relapse rate was about 8% and the side effect rate was very low. Levofloxacin was extremely successful in this setting which compares very favourably to results achieved by amoxicillin-clavulanate, and probably somewhat better than the results seen with the new macrolides such as azithromycin or clarithromycin. If all other characteristics of levofloxacin are considered, such as its excellent compliance, good side effect profile, and very rapid bactericidal activity, it can be concluded that levofloxacin is an excellent agent in this setting. It avoids the need to give multiple doses of a beta-lactam/beta-lactamase inhibitor and I think levofloxacin is an excellent choice for these patients.

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Q5. What role do you see levofloxacin playing in lower respiratory tract infections (LRTIs) and again contrast this to other agents?

A5. Levofloxacin has a real place in the therapy of acute CAP, especially when S. pneumoniae is suspected or known to be present. When I have to make a choice of antimicrobial therapy for patients with pneumonia, I prefer to identify the pathogen rather than treat empirically. However, even if I have identified the organism as probably S. pneumoniae based on Gram-stain, one has to be extremely cautious in choosing therapy because of the problem of penicillin-resistant pneumococcus. Data from Thornsberry and the Centers for Disease Control (CDC) clearly indicate that penicillin-intermediate or -resistant levels of S. pneumoniae occur as much as 30% of the time (Table 2)(9).

Table 2. Comparison of antimicrobial resistance to Haemophilus influenzae and Streptococcus pneumoniae in various regions of the United States
Table_2

This certainly causes a problem for the clinician who has a severely ill patient with an acute CAP in an area with likely resistance to penicillin. The choices then are to give frequent doses of a short half-life beta-lactam like cefotaxime, to give ceftriaxone in a high dose or to choose an agent like levofloxacin which retains its activity against penicillin-resistant S. pneumoniae. Most clinicians would initiate therapy with a drug that will be effective against a probable resistant organism, and this is why I prefer levofloxacin in this setting. As far as other common LRTI pathogens, obviously Moraxella and Haemophilus are going to be exquisitely sensitive to levofloxacin making it a very good choice treating these infections. For patients with suspected Legionella, I prefer fluoroquinolones over all other therapies. I dont believe that macrolides are the best choice in this setting.

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Q6. In which patients would you use oral versus IV therapy, and could you comment on the use of sequential therapy using levofloxacin (IV switching to oral) and the advantages this offers the physician in the treatment of RTIs?

A6. When patients with a more serious potential for morbidity present with pneumonia, they should be hospitalized and given IV therapy. In that setting, levofloxacin by vein is an appropriate starting therapy which can be switched to oral administration usually after 2-3 days. Due to the pharmacokinetic characteristics and the fact that levofloxacin has such an exceptionally high gastrointestinal absorption, the switch from IV to oral therapy is very simple and convenient. Other younger, relatively well patients can be treated with oral therapy in the outpatient setting. However, there remains the problem of what to do with the 55-year-old smoker who is not seriously ill, does not require hospitalization, but who the clinician is concerned about. In this patient, I would not use a macrolide as oral therapy, and I would not use a beta-lactam because of concern about possible penicillin-resistant S. pneumoniae. I think an oral fluoroquinolone would be very important for these patients along with close telephonic and, if necessary, physical follow-up in the first two days of therapy.

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Q7. It has recently been reported that macrolides are not an ideal empirical therapy for CAP. Would you agree with this?

A7. Most serious bacterial pneumonias are due to S. pneumoniae, and the clinician has to consider the risk of not covering a penicillin-resistant organism in a patient in whom morbidity could be high. I therefore use an agent that is more likely to treat penicillin-resistant S. pneumoniae pending susceptibility, and for that reason, I would never give a macrolide. The macrolide-resistance rate in the presence of penicillin resistance is 30-40%. Macrolides are suitable for milder infections which are less likely to be due to S. pneumoniae (Table 3)(10).

Table 3. Microbiology of community-acquired pneumoniaa
Table_3

However, the characteristics they possess, such as oral administration allowing outpatient care, are also features of oral levofloxacin therapy. Macrolides are not appropriate unless a macrolide sensitive organism has been identified. So for empiric therapy or in cases with a positive Gram-stain for S. pneumoniae, I do not use a macrolide, particularly in patients with other underlying co-morbidity factors.

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Q8. Could you comment on the activity of levofloxacin against biofilm-forming bacteria such as Pseudomonas aeruginosa, and how this compares with other antibacterials?

A8. Biofilm is a function of alginate production by P. aeruginosa, and during this time, the organisms are replicating less rapidly. Therefore, there are two problems: first, the ability of a drug to get through the biofilm to the actual organism, and secondly, to act against organisms which are not metabolizing rapidly, a problem which beta-lactams have. Levofloxacin has the characteristics which allow it to get through this biofilm, while most other antibiotics are trapped at the surface or in the biofilm. However, levofloxacin has only intermediate activity against P. aeruginosa itself, so while not fully effective, potentially it does a better job than many other agents (11).

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Q9. The atypical pathogens are often being cited as becoming more of a clinical problem in RTIs. Could you comment on the use of levofloxacin against these pathogens?

A9. Levofloxacin in vitro is active against C. pneumoniae and M. pneumoniae, certainly well within achievable plasma concentrations. These organisms exist in the cells, or on the surface of the respiratory tract. An advantage of the fluoroquinolones over the other agents is their ability to inhibit or kill both intracellular pathogens and pathogens which are not replicating very rapidly, which is probably the case with M. pneumoniae. Results from a large clinical trial evaluating patients with CAP, demonstrated over 60 determinations of C. pneumoniae or M. pneumoniae as causative pathogen, and treatment with levofloxacin achieved a greater than 95% success rate (2). Supporting evidence for the efficacy of levofloxacin is derived from studies evaluating its parent compound, ofloxacin. It is well known that ofloxacin is very effective against Chlamydia at other body sites. It is also known that levofloxacin reaches extremely high levels and persists in the respiratory tract achieving rapid reduction in the inoculum, so I would expect levofloxacin to be effective in treating these infections, but we need more definitive studies to confirm this.

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Q10. What is the activity of levofloxacin against Legionella species and could you compare this with other agents?

A10. Levofloxacin in vitro, in appropriate liquid and agar media, has exquisite activity against L. pneumophila. Levofloxacin concentrates from six to eight times in both polymorphonuclear and mononuclear phagocytes, and we know both extracellular and intracellular activity are impressive and far superior in persistence compared to rifampicin. Also, in terms of rapid reduction in bacterial count, levofloxacin is superb compared to a macrolide like erythromycin. One would expect to see MIC90s in most Legionella test media of between 0.015-0.03 µg/ml for levofloxacin, and its activity is comparable against non-pneumophila strains. It is known that L. pneumophila is resident in macrophages of the respiratory tract. Several studies show unequivocally that the intracellular activity of the fluoroquinolones against L. pneumophila is excellent and levofloxacin in general is a superior drug in that setting. Therefore, levofloxacin has very good in vitro activity against Legionella, penetrates intracellularly, and possesses persistent activity which provides levofloxacin with significant advantages in treating these infections (Table 4)(12).

Table 4. Effects of fluoroquinolone antibiotics and erythromycin on the intracellular multiplication of Legionella species at 1x and 8x the MIC
Table_4

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Q11. You performed a study investigating the effect of levofloxacin, erythromycin and rifampicin pretreatment on growth of L. pneumophila in human monocytes. Could you describe your study and its aim?

A11. In our study, we were interested in two distinct phases of Legionella pathogenesis. The first is that although Legionella is recognized as an intracellular pathogen, it does kill the phagocyte and move onto other cells. So, during its pathogenesis, there is an extracellular phase. We were very interested in studying whether, during the extracellular phase, interaction between the antibiotic and organism might have any favorable or unfavorable effects. We therefore studied levofloxacin and compared it to erythromycin and rifampicin in the treatment of L. pneumophila at 1, 2, or 4 times the MIC. Legionella were treated with antibiotic then washed free of the antibacterial agent before being added to phagocyte culture. The degree and rate of regrowth was then assessed (13).

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Q12. What were the results of your study?

A12. We found that, even at 4 times the MIC, levofloxacin not only reduced the inoculum, but also significantly decreased the amount and rate of regrowth when compared to the controls (Figure 1)(13).

Figure 1. Geometric mean count of CFU/ml at days 0, 1, 2 and 3 after the pretreatment of Legionella pneumophila.
Figure_1

These differences were dramatically different compared to the effects of rifampicin and erythromycin, so levofloxacin had a unique effect after only a brief exposure to the organisms prior to phagocytosis. We believe this indicates a probable PAE and surprisingly long residual activity, making levofloxacin an important choice for treating serious infection due to L. pneumophila. When one compares the administration of levofloxacin in this setting to erythromycin by vein, there is no choice; levofloxacin is potentially far superior not only because of its activity, but also its ease of administration, cost-effectiveness and excellent safety profile. When treating seriously ill older individuals with legionellosis, I would apply the pharmacologic model of Preston and Drusano to choose the optimal dose of levofloxacin, which may need to be greater than the usual 500 mg once-daily dose. Higher doses are also well tolerated.

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Q13. Do you see any situations in which combination therapy using levofloxacin plus another agent may be indicated?

A13. When there is the possibility of an anaerobic infection, it would be necessary to add an agent with anti-anaerobic activity. Secondly, when treating a possible Pseudomonas infection, I would add a beta-lactam with antianaerobic as well as antipseudomonal activity. Although, there is no evidence for synergistic activity with this combination, I believe that additive effects should be expected. There is also intriguing data about metabolites of clarithromycin in combination with levofloxacin having additive activity against L. pneumophila, although this is not proven clinically as yet.

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Q14. How does the safety and tolerability of levofloxacin compare to other agents?

A14. The highest reported side effect rate of levofloxacin, of up to 9%, compares very favorably with both beta-lactams and macrolides. Levofloxacin is extremely safe. In comparison to newer agents, such as clinafloxacin and sparfloxacin, I believe levofloxacin is going to have a better tolerability profile, as it is less of a photosensitiser than the other two agents.

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Q15. In some chronic RTI, longer treatment schedules are required. Could you discuss the safety of levofloxacin in this situation?

A15. The best data assessing long-term levofloxacin therapy come from Japan. This relates to the treatment of panbronchiolitis, where patients received months of therapy with no major problems. In fact, long duration levofloxacin was well tolerated. Multiple-dose, high-dose studies conducted by pharmacologists have also demonstrated that the long-term tolerability and safety of levofloxacin is good. This is in contrast to macrolides which can have problems interfering with the metabolism of other drugs if given for extended periods.

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Q16. Does levofloxacin offer specific advantages to the physician and patient over other agents in the treatment of immunocompromized patients?

A16. My approach to the immunocompromized patient with pneumonia depends on the fact that microbiological diagnosis leads to a better outcome. Therefore, if the microbiological diagnosis supports fluoroquinolone use, I would certainly administer levofloxacin, using its advantageous characteristics of good bactericidal activity, rapid reduction of inoculum, good tissue penetration, and lack of interference with other agents, to achieve the best result possible. If the pneumonia is focal and bacterial in quality, I would give levofloxacin because of the possibility of legionellosis as many immunocompromized patients with T cell deficiency are highly at risk for legionnaire disease.

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Q17. If you were asked to briefly summarize the relative advantages levofloxacin has over other antibiotics in the treatment of RTIs, what would you say?

A17. Levofloxacin offers the clinician and patient an excellent therapy for bacterial RTIs. It can be given in a single daily oral dosing schedule, does not interfere with other drugs which many elderly patients are also taking, and has a very good side effect and toxicity profile. Levofloxacin has an excellent and rapid bactericidal activity and long tissue persistence with a residual antibacterial effect. The spectrum of activity of levofloxacin also includes penicillin-resistant S. pneumoniae, ensuring that levofloxacin represents an extremely good drug in these infections, much more than macrolides and obviously beta-lactams. Respiratory tract infections are high inoculum infections, and we need to treat them with agents that achieve inhibitory activity for as much of the 24-hr cycle as possible. Due to its excellent pharmacokinetic and pharmacodynamic profile, levofloxacin does achieve sustained levels of activity, making it one of the most favorable of the new fluoroquinolones to enter the market.

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References

  1. Hofmann J, Cetron MS, Farley MM, Baughman WS, Facklarm RR, Elliott JA, Deaver KA, Breiman RF. The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta. N Engl J Med 1995; 333: 481.
  2. File TM Jr, Segreti J, Dunbar L, Player R, Kohler R, Williams RR, Kojack C, Rubin A. A multicenter, randomized study comparing the efficacy and safety of intravenous and/or oral levofloxacin versus ceftriaxone and/or cefuroxime axetil in treatment of adults with community-acquired pneumonia. Antimicrob Agents Chemother 1997; 41: 1965-72.
  3. Lee LL, Sha X, Gotfried MH, Howard JR, Dix RK, Fish DN. Penetration of levofloxacin into lung tissue after oral administration to subjects undergoing lung biopsy or lobectomy. Pharmacotherapy 1998; 18: 35-41.
  4. Andrews JM, Honeybourne D, Jevons G, Brenwald NP, Cunningham B, Wise R. Concentrations of levofloxacin (HR 355) in the respiratory tract following a single oral dose in patients undergoing fibre-optic bronchoscopy. J Antimicrob Chemother 1977; 40: 573-7.
  5. Licata L, Smith CE, Goldschmidt RM, Barrett JF, Frosco M. Comparison of the postantibiotic and postantibiotic sub-MIC effects of levofloxacin and ciprofloxacin on Staphylococcus aureus and Streptococcus pneumoniae. Antimicrob Agents Chemother 1997; 41: 950-5.
  6. Visalli MA, Jacobs MR, Appelbaum PC. Susceptibility of twenty penicillin-susceptible and -resistant pneumococci to levofloxacin, ciprofloxacin, ofloxacin, erythromycin, azithromycin, and clarithromycin by MIC and time-kill. Diagn Microbiol Infect Dis 1997; 28: 131-7.
  7. Preston SL, Drusano GL, Berman AL, Fowler CL, Chow AT, Dornseif B, Reichl V, Natarajan J, Wong FA, Corrado M. Levofloxacin population pharmacokinetics and creation of a demographic model for prediction of individual drug clearance in patients with serious community-acquired infection. Antimicrob Agents Chemother 1998; 42: 1098-104.
  8. Sydnor TA, Kopp EJ, Anthony KE, LoCoco JM, Kim SS, Fowler CL. Open-label assessment of levofloxacin for the treatment of acute bacterial sinusitis in adults. Ann Allergy Asthma Immunol 1998; 80: 357-62.
  9. Thornsberry C, Ogilvie P, Kahn J, Mauriz Y, and the Laboratory Investigator Group. Surveillance of antimicrobial resistance in Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis in the United States in 1996-1997; Respiratory Season. Diagn Microbiol Infect Dis 1997; 29: 249-57.
  10. Fine MJ, Smith MA, Carson CA, Mutha SS, Sankey SS, Weissfeld LA, et al. Prognosis and outcomes of patients with community-acquired pneumonia: A meta-analysis. JAMA 1995; 294: 134.
  11. Yassien M, Khardori N, Ahmedy A, Toama M. Modulation of biofilms of Pseudomonas aeruqinosa by quinolones. Antimicrob Agents Chemother 1995; 39: 2262-8.
  12. Stout JE, Arnold B, Yu VL. Comparative activity of ciprofloxacin, ofloxacin, levofloxacin, and erythromycin against Legionella species by broth microdilution and intracellular susceptibility testing in HL-60 cells. Diagn Microbiol Infect Dis 1998; 30: 37-43.
  13. 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 Antmicrob Chemother 1997; 40: 673-78.

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