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toumei ../image Congress Report

The 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy
September 2730, 2002
San Diego, CA, USA

CONTENTS

Introduction

Breaking the dosing paradigm: can fluoroquinolone dosing be safely increased to improve outcome

Scientific rationale behind higher fluoroquinolone dosing

Safety considerations when increasing fluoroquinolone dosing

Clinical application of high-dose fluoroquinolone therapy

PD analysis of high-dose levofloxacin in nosocomial pneumonia

PK data for levofloxacin in children

Levofloxacin effective in treating Mycoplasma pneumoniae infections

Levofloxacin: proven efficacy in prevention and treatment of anthrax

Relationship between fluoroquinolone use and resistance


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Introduction

The 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy (42nd ICAAC), recently held in San Diego, from September 27-30, 2002, carried on the tradition of providing participants with an infectious disease forum of unsurpassed breadth and depth. Barbara E. Murray, Chair, ICAAC Program Committee, University of Texas Medical School, Houston, TX, USA described the 42nd ICAAC as "offering scientific excellence through peer-reviewed presentations, and that the meeting was acknowledged as the major international venue on antimicrobial agents and infectious diseases". The wide range of sessions available allowed all attending to become familiar with the latest developments in their own particular subspecialties, and encouraged enthusiastic interaction between physicians, clinical microbiologists, pharmacists, and healthcare professionals from all corners of the globe. Leading researchers and clinicians focused on a number of important areas, with new information on bioterrorism, as well as ongoing results from surveillance studies, and latest clinical applications of antimicrobial research. Antibiotic resistance and nosocomial infections were areas generating a lot of interest, as was the use of pharmacodynamic and pharmacokinetic techniques, providing clinicians with ra-tional tools for optimizing antimicrobial therapeutic strategies. The following provides a summary of highlights related to infectious diseases, with particular reference to the increasing role of the newer fluoroquinolones.


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toumei ../image Breaking the dosing paradigm: can fluoroquinolone dosing be safely increased to improve outcome

Over the past decade, the role of fluoroquinolones has continued to expand, with interest in these compounds rising at a staggering rate. This has been coupled with a significant increase in usage of these agents, and in the recent past, the spotlight has firmly focused on the newer "respiratory" quinolones, best exemplified by levofloxacin. Among the many sessions looking at these agents, one symposium that stood out was that sponsored by the Northeastern Ohio Universities College of Medicine, with an educational grant from Ortho-McNeil Pharmaceutical, Inc., Raritan, NJ, USA, which aimed to provide scientific and clinical rationale for extended fluoroquinolone dosing. Chaired by Dr. Jack Remington, Professor, Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, CA, USA, this meeting looked at pharmacodynamic (PD) data for optimizing drug dosage, safety considerations, and clinical applications of high-dose therapy. Dr. Remington described the faculty as outstanding, and the presenters as world-recognized experts in their fields, providing participants with a unique opportunity to understand high-dose therapy, described by the Chairman as "the new paradigm in fluoroquin-olone pharmacotherapy".

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toumei ../image Scientific rationale behind higher fluoroquinolone dosing

The first speaker in the symposium was Dr. George L. Drusano, Professor and Director, Division of Clinical Pharmacology, Departments of Medicine and Pharmacology, Albany Medical College, Albany, NY, USA. In setting the scene, Dr. Drusano described the scientific rationale behind higher fluoroquinolone dosing, aimed at maximizing the probability of a good clinical and/or microbiological outcome, while minimizing the probability of a concentration-related adverse event. Obtaining higher AUC/MIC ratios is a key issue in this strategy, as all principal endpoints have been linked to specific AUC/MIC values. Once these target ratios have been defined, the question of how often a specific drug dose will achieve that target for pathogens of clinical interest needs to be an-swered. Factors affecting this include;

  • the magnitude of the target to be attained (size of AUC/MIC ratio required)
  • pharmacokinetic (PK) variability (patient characteristics)
  • pathogen MIC variability
  • degree of protein binding.
       Dr. Drusano began by reviewing the data, while pointing to the importance of dose size in attaining higher AUC values and therefore higher AUC/MIC ratios for specific MICs. Studies by Peloquin and Fink in nosocomial pneumonia have demonstrated that for the fluoroquinolone, ciprofloxacin, dose size does matter. Following on from this initial work, Dr. Drusano's group investigated two different inocula of Pseudomonas aeruginosa in a mouse-thigh infection model. They found that when there was a low pathogenic inoculum, an AUC/MIC ratio of 14 was sufficient to shut off bacterial growth. However, when a higher inoculum was used, the necessary AUC/MIC ratio required to stop growth increased to almost 45. This effect was hypothesized to be due to the emergence of resistance and the mutational frequency of resistance. That is, if there are two subpopulations in the total population - susceptible and resistant subpopulations - the drug exposure will have differential effects on them. This situation was modeled using mathematical techniques, and results demonstrated that to prevent the emergence of a resistant P. aeruginosa mutant population, an AUC/MIC ratio of 157 is required. Dr. Drusano's group then validated this by using two different doses of levofloxacin that had not been trialled before and a time period 24 hr longer than used previously. Results demonstrated that a good log kill of the total population was achieved, dropping from a high of almost 8 log10 CFU/g of tissue to between 5-6 log10 CFU/g of tissue. After treatment, regrowth occurred, but at 48 hr, the total population was reduced from the original base by three-quarters of a log. More indepth analysis revealed that the resistant subpopulation actually increases in size during this time. If a sufficiently high AUC/MIC ratio is achieved, however, this growth of the resistant subpopulation will not occur.
       Further investigation into this resistant subpopulation with sequencing of the quinolone resistance-determining region (QRDR) of gyr A/B and par C/E revealed no mutations compared with baseline. The mutant strains were then evaluated using Microcide mex system pump inhibitors and the organisms showed an expression profile that was a mixture of mex AB-opr M, mex CD-opr J and mex EF-opr N, with the mex EF-opr N dominant in the early time period (< 10 hr untreated). In treated animals, there was early expression of mex EF-opr N, and after 28 hr, this was replaced by mex CD-opr J. One hypothesis proposed for these findings is that there is an interaction between expression of mex system pumps and the probability of attaining a target mutation. This investigation provided insight into how the overall (susceptible plus resistant) population responds to pressure from levofloxacin, and more importantly, allowed a model of the resistant subpopulation to be developed, which was then used to choose a dose based on suppressing the resistant mutants. The prospective validation demonstrated that the doses chosen to encourage and suppress the resistant mutants did work.
       Dr. Drusano then described results of studies that had used clinical and microbiological outcome as study endpoints. A 1993 Forrest study demonstrated that cure was optimized when an AUC/MIC ratio of > 125 was achieved. Clearly, as the AUC/MIC ratio increases, the probability of a good clinical outcome or microbiological outcome increases up to a maximum value. As AUC equals dose/drug clearance, a larger dose will yield higher AUC values. For any specific MIC, a higher AUC will produce a higher AUC/MIC ratio and, therefore, a higher probability of good outcome.
       By knowing how a population will act and then developing full distribution profiles of individual patients, Monte Carlo simulation allows examination of how effective a specific dose will likely be. This has led to Monte Carlo simulation studies aimed at determining how good a higher dose is going to be for common Gram-negative nosocomial pathogens. In one study described by Dr. Drusano, 35 volunteers were treated with levofloxacin 750 mg and their PK parameter values recorded (Table 1). Using the mean clearance of 7.92 l/hr, a model that created 10,000 simulated subjects analyzed what their AUC would be. The model predicted how often the target AUC/MIC ratio of 125 would be achieved, and also demonstrated that for MIC90 values < 1, a target attainment of 100% is achieved, but this drops rapidly at an MIC90 of 1. The model then allows an expectation of MIC90s likely to be found to be used, and demonstrates how likely the drug will hit the target in the real world accounting for all distributions. Using 404 strains of P. aeruginosa, 550 Klebsiella pneumoniae, and 297 Enterobacter cloacae, study results revealed that levofloxacin achieved 60%, 92%, and 87% target attainments for these three pathogens, respectively. Levofloxacin 750 mg o.d. IV in volunteers was equivalent to ciprofloxacin 400 mg IV q12hr from data in ICU patients for target attainment in the Gram-negative pathogens that most frequently cause nosocomial pneumonia. Results for levofloxacin 750 mg o.d. were also virtually identical to those associated with ciprofloxacin 400 mg IV q8hr. Thus, Dr. Drusano concluded that clearly, with the endpoints examined here, the probability of a "good" outcome increases with the AUC/MIC ratio (up to a maximum) and hence, with an increase in dose.

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    Table 1. Population pharmacokinetic parameter values for 35 volunteers receiving levofloxacin 750 mg IV

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    toumei ../image Safety considerations when increasing fluoroquinolone dosing

    With the PD data supporting better outcome with greater levofloxacin dose, the issue of safety in clinical situations then needed to be addressed. Dr. Keith A. Rodvold, Professor of Pharmacy Practice, University of Illinois, Chicago, IL, USA looked at this issue. Dr. Rodvold noted that the need to use a higher dose in certain situations is dependent on the specific patient populations and type of infections. To define the most appropriate dose, he quoted Ambrose, saying "an understanding of the integration of target patient population PK and the MIC distribution is crucial for selecting effective dosage regimens, especially in the setting of empirical therapy". At the same time, other clinicians have countered this approach by saying, "the appropriate dose is to reduce the risk of side effects, the potential for superinfection, and the cost of therapy; generally, the lowest dose of an antibiotic that will be effective is used".
       Fluoroquinolones, while having class adverse drug reactions (ADRs), also have been associated with some specific problems ranging from 1992 with the withdrawal of temafloxacin, through to 1999 with the QTc labeling put on moxifloxacin and gatifloxacin. Most of these ADRs, except one, occur as a syndrome or event and are not associated with dose dependency. The benefits of a higher fluoroquinolone dose include protection against resistance development, and improved survivorship. When levofloxacin was first introduced, it was prescribed as a q12hr schedule, but in 1996, the US Food and Drug Administration (FDA) approved a 500 mg o.d. schedule, and then in September 2000, levofloxacin 750 mg o.d. was approved for complicated skin and soft-tissue infections (SSTIs). The higher doses, given in a once daily regimen, have not changed the ADR profile, with the overall incidence, type, and distribution of ADRs similar in patients receiving levofloxacin 750 mg o.d. compared to those receiving levofloxacin in doses from 250 mg o.d. to 500 mg b.i.d.
       However, fluoroquinolone cardiotoxicity appears to be dose dependent, with a strong suggestion that as the exposure to moxifloxacin increases from 400-800 mg, the percentage of prolonged QTc increases. Studies have been performed to investigate this issue with levofloxacin. In one trial, the mean QTc change from baseline was assessed in volunteers administered levofloxacin 500 mg, 1,000 mg and 1,500 mg doses compared to placebo (Table 2). It was not until the dose was increased to 1,500 mg before a statistically significant difference from placebo was reported. There is a doubling of prolongation time from the 500 mg to 1,000 mg doses; therefore, 750 mg is probably not at the crux of where dose dependency occurs. The second trial doubled the usual dose of levofloxacin, ciprofloxacin, and moxifloxacin and compared these to placebo. Levofloxacin and ciprofloxacin appeared to be very safe, but the increase in QTc prolongation when the moxifloxacin dose was increased differed significantly from the other two fluoroquinolones as well as from the placebo.
       Clinical results also support the safety of high-dose levofloxacin, with preliminary data from a nosocomial pneumonia trial demonstrating that emergent ADRs associated with levofloxacin 750 mg o.d. and imipenem were similar. Thus, the overall safety profile of levofloxacin remains essentially unchanged including when the higher dose of 750 mg is used. Potential pathogens, clinical indications, and duration of therapy where the higher dose of levofloxacin is useful are now being explored.


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    Table 2. Mean change in QTc from baseline in two trials

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    toumei ../image Clinical application of high-dose fluoroquinolone therapy

    Dr. Thomas M. File Jr., Professor of Internal Medicine, Northeastern Ohio Universities College of Medicine, and Chief, Infectious Disease Service, Rootstown, OH, USA presented the rationale and clinical application of high-dose therapy. He described this strategy as providing the opportunity to maximize and exploit concentration-dependent killing. Higher doses achieve higher Cmax and AUC/MIC values, allowing treatment of difficult pathogens, while also increasing penetration into various tissues and fluids, and preventing the development of resistance. It is also potentially associated with a shorter duration of therapy with improved compliance and convenience, but this must be assessed in conjunction with safety considerations.
       Current clinical applications for high-dose fluoroquinolones include severe complicated lower respiratory tract infections (LRTIs), nosocomial pneumonia, severe complicated SSTIs, bone and joint infections, empirical therapy in febrile neutropenic patients, complicated intra-abdominal infections and gynecologic and pelvic infections. Dr. File then turned his attention to the use of levofloxacin high-dose therapy for managing nosocomial pneumonia. The most common pathogens responsible for this include Haemophilus influenzae, Staphylococcus aureus, and P. aeruginosa, with variable susceptibility depending on location and patient type. Choosing the correct empiric therapy once nosocomial pneumonia is diagnosed is extremely important, as appropriate initial antibiotic therapy is a vital factor in determining outcome, with mortality decreasing only when appropriate therapy is initiated immediately.
       Clinical studies investigating high-dose levofloxacin have been performed. In the first one reported by Dr. File, levofloxacin 750 mg o.d. was compared to imipenem 500-1,000 mg q6-8hr, and if there was concern over P. aeruginosa, a second drug was added. Clinical and bacteriological results were comparable, as was the safety assessment. Interestingly, there were fewer super-infections with P. aeruginosa associated with the levofloxacin treatment.
       Three studies have investigated a daily dose of levofloxacin of 1,000 mg. The first compared levofloxacin 500 mg b.i.d. against imipenem 1,000 mg t.i.d. for sepsis, the second compared levofloxacin 500 mg b.i.d. versus ceftriaxone 4,000 mg o.d. for hospitalized patients with pneumonia, and the third, a three-armed study, compared levofloxacin 500 mg b.i.d. with levofloxacin 500 mg o.d. versus amoxicillin-clavulanic acid 625 mg t.i.d. for community-acquired pneumonia (CAP). The results found that levofloxacin 500 mg o.d. was as effective as levofloxacin 500 mg b.i.d. in CAP. There were no statistical differences in clinical and microbiological outcomes, or in the rate of ADRs among the studies.
       Another published study reported by Dr. File investigated high-dose levofloxacin versus ticarcillin-clavulanic acid for complicated SSTIs, usually in patients with underlying significant problems like diabetes. Levofloxacin was administered in a 750 mg o.d. IV-PO regimen, and ticarcillin-clavulanic acid in a 3,100 mg q4-6hr IV regimen, switching to amoxicillin-clavulanic acid PO. The clinical response and ADR rates were comparable, but the bacteriological response was better with levofloxacin, mainly due to the greater efficacy of levofloxacin in treating S. aureus (Table 3).
       One additional potential advantage of high-dose levofloxacin therapy is to shorten the duration of therapy. In addition, by reducing the duration of antimicrobial exposure, such therapy has the potential to reduce the risk of ADRs, decrease the development of resistance, increase patient compliance, and decrease overall cost. To date, there has been an accepted practice of treating RTIs for 7-10 days, but this is now being questioned. A study published in 2001 by the Centers for Disease Control investigated short-course high-dose therapy versus standard amoxicillin therapy for RTIs. Part of the study analyzed nasopharyngeal colonization a month later, and found that colonization with penicillin-resistant Streptococcus pneumoniae (PRSP) was significantly less with the shorter 5-day duration of therapy than the standard 7-10 days. Dr. File quoted this paper as saying, "If treatment regimens can be modified to minimize carriage of PRSP while maintaining clinical efficacy, encouraging such prescription practices represents a low-cost feasible intervention to limit the spread of resistance in developing countries as well as here; short-course high-dose therapy, which resulted in both improved adherence and decreased risk of PRSP carriage, appears promising as a complement to other approaches for managing the spread of resistant S. pneumoniae, such as appropriate antibiotic use campaigns and introduction of the pneumococcal conjugate vaccine."
       Another study just completed looked at short-course high-dose levofloxacin (750 mg o.d. for 5 days) versus levofloxacin 500 mg o.d. for 10 days. Results indicated that clinical and microbiological outcomes were comparable between arms. Thus, Dr. File summarized by stating that increased fluoroquinolone therapy can be applied to multiple clinical scenarios if the drug's ADR profile allows. The potential exists to improve efficacy and safety, and to minimize resistance, making short-course high-dose therapies attractive therapeutic options, and these regimens are likely to be an important future strategy.


      Table 3. Levofloxacin 750 mg o.d. versus ticarcillin-clavulanic acid 3,100 mg q4-6hr for the treatment of complicated skin and soft tissue infections: clinical response and microbiological eradication
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    PD analysis of high-dose levofloxacin in nosocomial pneumonia

    While it is well known that levofloxacin possesses excellent clinical and microbiological efficacy in the treatment of most RTIs, including CAP, acute exacerbations of chronic bronchitis (AECB), and rhinosinusitis, there is less data available on the outcome following levofloxacin therapy in nosocomial pneumonia. Adding to the PK/PD data presented by Dr. Drusano were results from a joint study he undertook with Dr. Sandra L. Preston et al., Albany Medical College, Albany, NY, USA, in 58 ICU patients with nosocomial pneu-monia, treated with either 750 mg levofloxacin or imipenem. Nine patients (15.5%) with P. aeruginosa received combination therapy with a -lactam. Complete data was available for 47 patients, in order to assess outcome, plasma-concentration-time data, and determination of MIC for the causative pathogen. Results revealed the serum drug clearance to be 7.238 ± 4.36 l/hr and volume of distribution to be 34.42 ± 33.51 l, in the central compartment. PD analysis demonstrated that there was a high correlation between the predicted and observed values of levofloxacin concentration in the patients. For the 58 patients, clinical outcome was 76% and microbiological outcome was 81%. When an AUC/MIC ratio of 88 was achieved, the eradication rate was 90% (OR = 12, p < 0.007) (Table 4). The PK data of levofloxacin in these seriously ill patients were different from those reported for volunteers, and researchers concluded that high-dose levofloxacin therapy achieved good results in this group of patients that are recognized as difficult-to-treat.


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    Table 4. Correlation between AUC/MIC breakpoint and microbiological eradication

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    PK data for levofloxacin in children

    An investigation into the PK of levofloxacin oral suspension in infants and children was performed by Dr. Shuchean Chien et al., Johnson & Johnson Pharmaceutical Research and Development, Raritan, NJ, USA and a number of Children's hospitals throughout the US. While levofloxacin has been approved for use in adults for infections in most body systems, like all fluoroquinolones, it has not been approved for use in children. This is due to the historical finding in animals that fluoroquinolone use appeared to be associated with joint arthropathy, although when used in compassionate cases, usually children with cystic fibrosis, this has not been reported to be a significant problem. Therefore, a single-dose, multi-center study was performed in children aged six months to 16 yr, stratified into five cohorts according to age. Patients received a single dose of levofloxacin 7 mg/kg PO (not exceeding 500 mg), with blood and urine samples taken over the next 24 hr. The following PK parameters were assessed; peak plasma concentration (Cmax), time to Cmax, half-life, AUC, volume of distribution, total body clearance, renal clearance, and amount excreted in urine as a percentage of the dose. Safety was also monitored, according to both clinical and laboratory findings. Forty of 41 children completed the study, with one subject withdrawn due to a mild ADR (i.e., vomiting). All other subjects tolerated the drug well. The suspension was readily absorbed, with lower clearance, and higher systemic exposure as age increased. The Cmax values were similar across all age groups, and plasma concentration versus time profiles were super-imposable between the 0.5-2-yr- and 2-5-yr-age groups, and between the 10-12-yr- and 12-16-yr-age groups. Due to faster clearance of levofloxacin in younger children, they may require different dosing regimens to achieve the same drug exposure as adults.

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    Levofloxacin effective in treating Mycoplasma pneumoniae infections

    CAP is recognized as being associated with a huge healthcare burden, and it is now reported that 25-50% of these infections are caused by Mycoplasma pneumoniae, depending on the type of patient population. In addition, this pathogen is responsible for many of the cases of tracheobronchitis, and is therefore associated with significant costs. The fluoroquinolones are the only likely bactericidal agents against this pathogen, and there-fore a study to assess the activity of levofloxacin against M. pneumoniae was performed by Dr. Lynn B. Duffy, Department of Microbiology, and Dr. Ken B. Waites, Professor of Pathology, Director of Clinical Microbiology, both from the University of Alabama at Birmingham, Birmingham, AL, USA. In addition, the activity of levofloxacin against four macrolide-resistant M. pneumoniae isolates was assessed. The MIC90s of 102 isolates of M. pneumoniae were determined, and MBCs (minimum bactericidal concentrations) were determined for 12 isolates, with 3 isolates tested by time-kill assay. Results indicated that all 102 isolates were inhibited by levofloxacin at < 2g/ml. There was no loss of activity over time. The MBCs for 10 of the 12 isolates were 2-4 × MIC90, which is indicative of bactericidal effect (Figure 1). Levofloxacin killed more than 99.9% of M. pneumoniae in < 72 hr at less than four times the MIC90, without significant regrowth. When tested against the erythromycin-resistant isolates, levofloxacin was shown to maintain activity. Thus, these in vitro results indicate that levofloxacin would be effective in treating M. pneumoniae infections, including seriously ill patients.


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    Figure 1. MIC/MBC of 12 Mycoplasma pneumoniae isolates against levofloxacin.

    Abbreviations: MIC = minimum inhibitory concentration, MBC = minimum bactericidal concentration.
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    Levofloxacin: proven efficacy in prevention and treatment of anthrax

    With the concern over bioterrorism using Bacillus anthracis, coupled with the potential for resistance to penicillin and -lactamases, researchers have been investigating other effective management strategies for dealing with this pathogen. To date, there has been little data on the antimicrobial susceptibility of this pathogen, but a study performed by Dr. Duygu Esel et al., Departments of Microbiology and Infectious Diseases, Kayseri, Turkey, shed more light on this. They investigated 40 clinical isolates of B. anthracis, measuring the susceptibilities to gatifloxacin, levofloxacin, ciprofloxacin, doxycycline, and penicillin G using National Committee for Clinical Laboratory Standards (NCCLS). The newer fluoroquinolones, levofloxacin and gatifloxacin, demonstrated good in vitro activity against all isolates, which was comparable to the other first-line agents tested. The MIC50 and MIC90 for levofloxacin were 0.06 g/ml and 0.12 g/ml, respectively. The two new fluoroquinolones can be considered effective therapy for post-exposure prophylaxis or for therapy of anthrax, in particular inhalation anthrax, due to their excellent penetration into respiratory tissues.

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    Relationship between fluoroquinolone use and resistance

    The in-depth analysis of resistance trends is gaining increasing data, with reports from around the world tracking antimicrobial susceptibility patterns presented at the latest ICAAC. One of the most interesting was a paper reported by Dr. George G. Zhanel et al., University of Manitoba, Winnipeg, MA, Canada, and Dr. Charles K. Chan et al., University of Toronto, ON, Canada, which analyzed outpatient antibiotic prescription data from January 1, 1997 to December 31, 2001, and compared this to S. pneumoniae resistance obtained from an ongoing Canadian Respiratory Organism Surveillance Study. It was clearly shown that during 1997-1998 to 2001-2002, total fluoroquinolone use had increased dramatically by 72.8%. Further differentiation between individual fluoroquinolones showed that while ciprofloxacin use had only increased by 20.2%, the amount of newer fluoroquinolones used over this period (levofloxacin, gatifloxacin, moxifloxacin) had increased by 10,500%. Analysis of the resistance of S. pneumoniae to fluoroquinolones revealed that during this time the resistance rate remained stable at approximately 1% (Table 5). Thus, researchers concluded that although the use had increased greatly, levofloxacin resistance in S. pneumoniae remains low.


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    Table 5. Distribution of levofloxacin MICs (g/ml) against Streptococcus pneumoniae in Canada from 1997-2002

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