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toumei ../image Congress Report

Highlights from the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy
September 14-17, 2003 Chicago, IL, USA

CONTENTS

Introduction

Preserving the fluoroquinolones

Resistance issues and trends of community-acquired respiratory infections

Trends in multi-drug resistance

Correlation between penicillin and macrolide resistance

Summary of TRUST 2003 surveillance data

Fluoroquinolones: Do they know where the infection is? Potential for collateral damage

Levofloxacin - providing a more targeted therapy

A change to levofloxacin associated with a reduction in the incidence of CDAD

New dosing paradigm: high-dose, short-course fluoroquinolone therapy for CAP

Fluoroquinolones: excellent pharmacokinetic/pharmacodynamic features for short-course, high-dose therapy

Levofloxacin: safe and cost-effective at higher doses

Resistance trends outlined: levofloxacin maintains its excellent activity

Ciprofloxacin but not levofloxacin selects for mutational resistance

Enhanced penetration of high-dose levofloxacin in critically ill patients

Renal role for levofloxacin

Levofloxacin: effective strategy against bioterrorism

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Introduction

Acknowledged as the premier international meeting on antimicrobial agents and infectious diseases, the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), was recently held from September 14-17, 2003 in Chicago, Illinois. The wide range of sessions and topics available provided an unparalleled scientific opportunity to attend peer-reviewed presentations and lectures from world-recognized experts. As an interdisciplinary form, ICAAC is able to encompass the complementary specialties involved in infectious disease management, including the latest data from laboratory-based research, microbiological analysis, clinical trial results as well as pharmacoeconomics and public health care issues. This ensures that ICAAC provides a comprehensive coverage of infectious diseases, able to shine a great deal of light on many of the perplexing topics facing physicians around the world. Following the trend of recent meetings, the latest ICAAC provided a significant update on the current resistance situation worldwide. In addition there was a great deal of interest in nosocomial infections, particularly respiratory tract infections (RTIs) due to the huge impact of SARS earlier in the year. With these seen as the most important issues facing clinicians, this paper reports on highlights from throughout the Congress, focusing upon RTIs, and optimal management strategies including those provided by the fluoroquinolones.

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toumei ../image Preserving the fluoroquinolones

One of the first sessions of the Congress was a CME (continuing medical education) symposium entitled, "Preserving the Fluoroquinolones: Clinical and Pharmacologic Strategies".
The moderator of the session, John Bartlett, Professor of Medicine, Johns Hopkins University School of Medicine, Maryland, noted that despite 15 years of clinical use, the fluoroquinolones remain effective agents for RTIs and are recommended first-line agents for select patients with community-acquired pneumonia (CAP). Professor Bartlett began by commenting that due to the advent of SARS, which he described as an extraordinary event in the history of medicine, the management of CAP would probably never be the same. Topics that have become of particular interest include epidemiological trends, infection control measures, advances in diagnostic tests, especially for Chlamydia pneumoniae, antibiotic selection, new management measures such as the four-hour treatment rule, vaccine development and bioterrorism including inhalation anthrax.
The epidemiological profile of SARS revealed that 92% of cases occurred in China, with more than 90% of all cases nosocomial in origin. The detection of the etiological microbe was described as an unbelievable story, with a global pooling of laboratory data, allowing the virus to be sequenced within one week and reproduced by three other laboratories the following day. The medical response required to deal with this problem was incredible, with exceptional cooperation between agencies and specialists, as they recognized the importance of a disease which had a mortality rate greater than 50% in those aged over 65 years.
In addition to the impact of SARS, health systems have recently been hit by bioterrorism, with anthrax scares resulting in a huge burden in terms of both medical manpower and economic consequences. With 1.2 million anthrax cultures processed in the US, it has become apparent that "an ounce of prevention requires a ton of work".
Another area that is important in the field of RTIs is the ongoing development of diagnostic tests. This is taking on even more importance with the move toward giving an antibiotic within four hours after first being seen. While antibiotics such as -lactams have been preferred for pneumococcal infections, there are often problems with resistance. In this situation, fluoroquinolones remain exceptionally useful agents, with very low rates of resistance and an unbeaten record in clinical results. While there have been reports of fluoroquinolone resistance in specific centers, this has created the perception that the role of fluoroquinolones may be decreasing. Professor Bartlett commented that this is simply not the case, with fluoroquinolones continuing to exhibit great efficacy. What is required is further data on appropriate drug dosing and how to best select antimicrobials which may have less of an ecological effect on bystander commensal bacteria, while actively treating the bacteria causing CAP.

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toumei ../image Resistance issues and trends of community-acquired respiratory infections

"The most effective strategy against antimicrobial resistance is to get the job done right the first time.... Thereby defeating resistance before it starts". This quote taken from the WHO publication, 2000 was used by Dr. Daniel Sahm, Chief Scientific Officer at Focus Technologies, in his presentation focusing on the trends in resistance seen in CAP. Using the latest data from Tracking Resistance in the United States Today (TRUST), the largest longitudinal continuous surveillance program, Dr. Sahm was able to provide an overview of resistance issues and common bacterial RTI pathogens. The TRUST study reports microbiological data that is updated yearly since first produced in 1996 when it was developed to monitor trends in resistance occurring since the approval of levofloxacin.
The large scope of the TRUST studies has resulted in very robust data derived from more than 32,000 Streptococcus pneumoniae isolates, 7,000 Haemophilus influenzae and 4,200 Moraxella catarrhalis isolates which provides susceptibility profiling and trends in resistance for these three major RTI pathogens.
Results from the latest 2003 database indicate that fluoroquinolones have maintained a very high level of activity against H. influenzae, with 100% of isolates susceptible to levofloxacin. While resistance to amoxicillin-clavulanic acid, ceftriaxone and cefuroxime axetil is also low, it has become apparent that only 70% of H. influenzae are susceptible to ampicillin due to -lactamase production and resistance to trimethoprim-sulfamethoxazole (TMP-SMX) is also approaching 30%.
Similar trends were reported for M. catarrhalis using MIC90 (a minimum inhibitory concentration at which 90% of isolates are inhibited) data. Again the fluoroquinolones maintain high activity, with levofloxacin maintaining a MIC90 of 0.06 g/ml. The only agent among those tested that demonstrated a high MIC was ampicillin (8 g/ml) again due to intrinsic -lactamase production.
Results from TRUST 2003 demonstrated that 99% of S. pneumoniae isolates are sensitive to levofloxacin, with 0.04% showing intermediate resistance and 0.96% resistance. In regard to other agents, 96% of isolates were sensitive to ceftriaxone, 93% to amoxicillin-clavulanic acid, 76% to cefuroxime axetil, 72% to azithromycin and erythromycin, 70% to TMP-SMX, and only 66% sensitive to penicillin, with 17% demonstrating high-level penicillin resistance and 16% intermediate resistance. There were no reports of vancomycin-resistant isolates according to MIC data.
When a trend analysis was performed using data from the last five TRUST surveys, it revealed that the rate of penicillin-resistant S. pneumoniae (PRSP) has remained at approximately 35%, while that for TMP-SMX has shown a slight decrease to 30%, and the macrolides have risen slightly over the five-year period to 28%. Therefore, the trends for these three classes of agents have tended to level off, but at what Dr. Sahm described as an unacceptably high non-susceptibility rate. In contrast, over the same time period the susceptibility of S. pneumoniae to ceftriaxone has remained at approximately 5% while that of levofloxacin has stayed very stable reflecting the continued activity of the fluoroquinolones without any substantial resistance to S. pneumoniae developing (Figure 1) .
This trend is supported by data from the last three TRUST studies, which illustrates the MIC distribution of levofloxacin. This demonstrates that there has been no statistically significant increase in levofloxacin MIC values of 2 g/ml or greater, with no left to right shift in the MIC population of S. pneumoniae (Figure 2) .


  Figure 1. Streptococcus pneumoniae antimicrobial resistance trends (1999-2003).
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  Figure 2. Levofloxacin MIC distribution: Streptococcus pneumoniae 2000-2003.
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toumei ../image Trends in multi-drug resistance

Analysis of multi-drug resistance (MDR) among S. pneumoniae using the TRUST surveillance data has also identified some interesting profiles. Antimicrobial agents tested included azithromycin, penicillin, TMP-SMX, levofloxacin, vancomycin and ceftriaxone. The percentage of MDR S. pneumoniae isolates between TRUST 6 (2001-2002) and TRUST 7 (2002-2003) dropped from approximately 14% to 12%, with the most common MDR phenotype being isolates resistant to three drugs (azithromycin, penicillin and TMP-SMX). When an isolate is resistant to four agents such as azithromycin, penicillin, TMP-SMX plus ceftriaxone the rate of resistance drops to only 2% and the rate of five-drug resistance has remained at undetectable levels, only occurring sporadically. Resistance to levofloxacin has only very rarely been involved.

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toumei ../image Correlation between penicillin and macrolide resistance

One of the findings that Dr. Sahm highlighted was the association between penicillin and macrolide resistance among S. pneumoniae. Although it is generally noted that these two resistance patterns occur side by side, regional patterns also indicate that while there are some overlap between penicillin and macrolide resistance, especially in the southeast US, in other areas this relationship is not clearly apparent. Therefore, while the strong association between penicillin and macrolide resistance continues it is not absolute.

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Summary of TRUST 2003 surveillance data

Resistance patterns among H. influenzae and M. catarrhalis have remained relatively unchanged over the last five years, and single and multiple drug resistance patterns among S. pneumoniae have leveled off, albeit at unacceptably high levels for certain drugs. Levofloxacin resistance remains uncommon, with the MIC distributions remaining concentrated in the less than 1g/ml range (greater than 98% of isolates). Levofloxacin resistance is not associated with any of the leading MDR phenotypes.

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Fluoroquinolones: Do they know where the infection is? Potential for collateral damage

Turning to the issue of ecological damage caused by antimicrobial treatment, Daryl Hoban, Professor of Medical Microbiology at the University of Manitoba, Canada, noted that antibiotics on the normal flora of the body can often inadvertently cause collateral damage. This effect is just starting to be more understood, and the impact of such a 'bystander' effect needs further assessment in order to choose the optimal agent when treating an infection. He noted, "Over the last decade, a broad consensus has emerged, recognizing that the future of antibiotic treatment will depend on the evolution of resistance, not only of pathogens targeted by therapy, but also, possibly mainly, among commensal organisms". Certainly recent research is showing that the transfer of resistant genes is possible between organisms that are effected by collateral damage and other organisms in the body.
Evaluation of the ecological impact encompasses the emerging spread of resistant genes and resistant strains as well as the modification and distribution of microbial populations in human commensal flora. Changes that are possible include effects on susceptible versus resistant organisms, overgrowth of organisms that may occur in the bowel or oropharynx and replacement of susceptible clones by resistant clones and transfer from patient to patient and between facilities.
One group of microbes studied in this regard is the anaerobes, which have possible roles in colonization resistance, nonspecific immunogenic stimulus, vitamin K production and bile acid deconjugation. This raises the questions that if anaerobes are beneficial why should we use aerobic antimicrobial agents that also possess anaerobic activity and does such treatment contribute to the development of resistance by inhibiting the normal anaerobic micro flora leading to overgrowth of other pathogens. A recent study by Lautenbach et al. assessed the impact of restricting vancomycin and third-generation cephalosporins on the prevalence of vancomycin- resistant enterococci (VRE). Results of this study demonstrated that the incidence of VRE increased despite restriction of vancomycin and third-generation cephalosporins and that clindamycin use was significantly associated with VRE. Therefore, this supports the hypothesis that anti-anaerobic agents may predispose to VRE spread. Results from the recent Donskey study also support this with patients already colonized with VRE, treated with an anti-anaerobic, reporting an increase in VRE compared to patients treated with a mild-minimal anaerobic agent who were found to have a drop in VRE.

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Levofloxacin - providing a more targeted therapy

The fluoroquinolones have differing anti-anaerobic activity with the MICs for a range of antimicrobials against Bacteroides fragilis indicating that this pathogen is more susceptible to moxifloxacin and gatifloxacin, while levofloxacin and ciprofloxacin have much higher MIC values. This has been supported by data coming out of colon models and kill curves to examine interaction of these agents with bowel commensals which indicate that levofloxacin does not exert a strong effect on bowel micro-flora. But if gatifloxacin and moxifloxacin are used there is a drop in the B. fragilis content of the gut and a sharp increase in vancomycin-resistant enterococci from 104 to 107-8 as well as a slight increase in Candida albicans (Figure 3) . It is also interesting to compare the fluoroquinolone activity against anaerobes in relation to their colonic concentration. While levofloxacin can achieve the highest serum concentrations compared to the other fluoroquinolones due to its renal excretion, the concentration of levofloxacin in the colon (4%) is much less than that achieved by moxifloxacin (25%) and ciprofloxacin (20-25%) and even gatifloxacin (5%). Ciprofloxacin and moxifloxacin are excreted at a rate greater than 1,000 g/g in the feces while the rates for gatifloxacin and levofloxacin were much lower at less than 100 g/g feces.


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Figure 3. Exposure of colonic flora to anaerobic agents: gatifloxacin 400 mg once daily or moxifloxacin 400 mg once daily.
Figure 3
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A change to levofloxacin associated with a reduction in the incidence of CDAD

Clostridium difficile-associated diarrhea (CDAD) is another side effect of anti-anaerobic treatment with some, but not all, agents with anti-anaerobic activity. For example clindamycin, ampicillin, and cephalosporins have been shown to be associated with this. The impact of changes in antibiotic policy on CDAD has been reported in a recent study. In this 1996 prescribing change, cefotaxime was replaced by ceftriaxone for initial treatment of severe sepsis or pneumonia. Over the following nine months the average number of patients with C. difficile toxin-positive stools per quarter increased from 16 to 39. Restrictions on the duration of ceftriaxone treatment was then introduced, and although this reduced usage by over 50%, CDAD continued at an average of 9.2 cases per month. In 1999 levofloxacin was substituted for ceftriaxone and the incidence of CDAD fell to 5 cases per month by 2000 (Figure 4). This indicates that a short duration of third-generation cephalosporin is associated with a similar risk for CDAD as a longer course. The six-month delay in the decline of CDAD after virtual withdrawal of cephalosporins may reflect a slowly diminishing environmental reservoir. The researchers concluded that there is a strong correlation between ceftriaxone consumption and the incidence of CDAD.
Another recent study has looked at this problem and compared the incidence of CDAD following treatment of lower respiratory tract infections (LRTIs) in hospitalized patients with levofloxacin or a -lactam. Nine hundred and thirty-eight patients were enrolled (490 patients treated with levofloxacin and 448 patients treated with cefuroxime axetil or amoxicillin). The incidence of CDAD was 3.8%, but in the levofloxacin group this was only 2.2% compared to 5.6% in the -lactam group (p < 0.01) particularly with cefuroxime axetil (9.2%, p < 0.0001). There was no significant difference in the incidence of CDAD between patients treated with levofloxacin or amoxicillin. The levofloxacin group had a significantly shorter duration of hospitalization (11.7 days, p < 0.01) compared with the -lactams (13.3 days), especially compared with the cefuroxime axetil group (16 days, p < 0.0000001). Patients with CDAD had a longer duration of hospital stay than those without CDAD (CDAD +ve 25.8 days, CDAD -ve 11.9 days, p < 0.0000001). Therefore levofloxacin is less likely to be the cause of CDAD and is associated with a shorter duration of hospital stay compared with -lactam-based therapy for LRTIs.
A paper by Miller at the 42nd ICAAC reported a high rate of nosocomial CDAD at a tertiary care hospital (incidence of 1.5/1,000 patient days). Infection control measures and restricted use of clindamycin were initiated but failed to impact on the rate of CDAD. However a decrease in cephalosporin prescribing with an increase in fluoroquinolone and ticarcillin-clavu-lanic acid use resulted in the rates of CDAD dropping to 0.6/1,000 patient days.
All of these studies indicate that antimicrobial therapy can be associated with unexpected and unwanted side effects caused by killing of normal commensal organisms. Therefore, before embarking on antimicrobial therapy of RTIs it is important to consider the unwanted collateral effects on bowel flora, and possible treatment options to minimize such effects. The unintended consequences of anti-anaerobic activity include collateral damage to normal bowel flora leading to prolonged VRE colonization, increased C. difficile and Candida albicans colonization. Clinicians may need to begin to formulate treatment strategies that minimize these effects, with levofloxacin therapy appearing to be safer in this regard.


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Figure 4. Ceftriaxone use and Clostridium difficile-associated diarrhea incidence.
Figure 4
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New dosing paradigm: high-dose, short-course fluoroquinolone therapy for CAP

Another strategy being proposed to minimize the emergence of resistance, while still maintaining excellent efficacy is that of high-dose, short-course fluoroquinolone treatment. Discussing this topic was Thomas File Jr., Professor of Internal Medicine, Northeastern Ohio Universities College of Medicine, Ohio. Beginning his presentation with a 27-year-old quote from Maxwell Finland, "We know everything about antibiotics except how much to give," Dr. File commented that not a lot had changed and today we are still trying to identify the best dose and duration of treatment. Ideal drug usage entails several factors including an accurate diagnosis, the correct drug, administration by the best route at the correct amount at optimum intervals for the required period.
A clear consensus on the optimal administration schedules is still required with no widely accepted duration of therapy for CAP advocated by all of the different official guidelines. In fact, the usual recommendations range from 7-21 days. It is now being proposed that a high-dose, short-course therapy will not only achieve a high cure rate but also lessen the development of resistance. Goals for short-course therapy include the eradication of pathogens, prevention of resistance, avoidance of adverse effects, while at the same time promoting convenience and cost-effectiveness.
One of the reasons for a short-course therapy schedule being attractive is the concern that prolonged therapy may be associated with increased resistance. A French study has shown that -lactams are associated with the emergence of resistance if used in an inappropriately low dose or for a long duration. Another study has investigated this problem among 795 outpatients in the Dominican Republic randomized to receive amoxicillin 90 mg/kg for 5 days or 45 mg/kg for 10 days. PRSP nasopharyngeal carriage was assessed and results showed PRSP carriage occurred in 24% using the short-course but in 32% of the standard course therapy. The clinical outcome was equivalent. Therefore short-course therapy was advantageous.
Additional research supporting short-course therapy is available from time-kill studies that demonstrate the great majority of bacterial killing (99%) occurs within the first 24 hours of appropriate antibiotic therapy. While there have been few studies of short-course therapy in pneumonia, one Nigerian study treated 73 patients with confirmed pneumonia for 24 hours after becoming afebrile. The mean duration of treatment was 2.5 days ranging from 1-5.6 days with a 100% cure rate. Researchers concluded that antimicrobial therapy could be stopped 24 hours after the patient has become afebrile. This is supported by work from Halm and co-workers who found that by day 2 of treatment, temperature had reduced to 38.5 in the majority of patients, and within three days temperature had reduced to 37.8.

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Fluoroquinolones: excellent pharmacokinetic/pharmacodynamic features for short-course, high-dose therapy

Agents that would be predictive for using in high-dose, short-course therapy include the fluoroquinolones, as this maximizes their concentration-dependent killing. Higher dose therapy using these agents is associated with higher maximum serum drug concentration (Cmax) and area under the concentration-time curve/MIC (AUC/MIC) values, increased bactericidal activity, thereby allowing the treatment of difficult pathogens. In addition, this schedule is associated with increased penetration into various tissues and fluids, and may prevent resistance due to less total drug exposure to both the patient and environment. However, before embarking on high-dose therapy safety issues need to be considered, and it is in this regard that differences among individual fluoroquinolones becomes apparent. One such fluoroquinolone that has been safely used in high doses is levofloxacin.
Administration of 750 mg levofloxacin is associated with an increase in pharmacodynamic parameters, with AUC rising markedly from 47.5 to 91 mg/h/l and peak serum concentration increasing from 5.7 to 8.6 mg/l. The concentrations in epithelial lining fluid increases from 9.9 to 22.1 g/ml, and the concentrations in alveolar macrophages increase from 97.9 to 105.1 g/ml.
The higher dose of levofloxacin may allow targeting of more resistant pathogens. This is supported by data from an in vitro kill-curve study of pneumococcal isolates resistant to ciprofloxacin. When an isolate is used with an MIC to levofloxacin of 1.8 g/ml there is little difference in kill rates between the 500 mg and 750 mg levofloxacin dose. However when an isolate is used with an MIC of 3.2 g/ml the 750 mg dose results in a much greater kill rate.

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Levofloxacin: safe and cost-effective at higher doses

Further data confirming the utility of the high-dose, short-course levofloxacin schedule has recently been reported in a sentinel study by Dunbar which compared 750 mg levofloxacin for five days versus a standard 500 mg dose for 10 days. Patient demographic characteristics were similar for both groups, with approximately 200 patients in each arm. Results demonstrated that the clinical success rates were comparable between these groups, with equivalent microbiological response rates (Table 1). In addition, the 750 mg arm was associated with a quicker resolution of symptoms, as assessed both objectively and subjectively. Data on file is also available to show that the higher dose was associated with a shorter time of intravenous therapy and quicker switch to oral administration, which then resulted in a cost saving for the 750 mg dose (Figure 5). There was no difference in adverse events between the 750 mg and 500 mg dose. Therefore short-course, high-dose levofloxacin achieves higher AUC/MIC and Cmax/MIC ratios with resulting clinical benefits including a more rapid resolution of symptoms and greater coverage of pathogens. Thus, available data indicate short-course therapy is effective, with potential to improve efficacy and safety and minimize resistance. It is a patient-friendly approach that is cost-effective and may prove to be an attractive therapeutic option for pneumonia.


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Table 1. 750 mg, short-course levofloxacin for community-acquired pneumonia: clinical success
Table 1

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Figure 5. Time from intravenous to oral switch therapy for 750 mg vs. 500 mg levofloxacin.
Figure 5
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Resistance trends outlined: levofloxacin maintains its excellent activity

The relationship between fluoroquinolone use and fluoroquinolone resistance in S. pneumoniae was investigated using Canadian data covering the six-year period 1997-2003. Dr. G. Zhanel, Health Sciences Centre, University of Manitoba reported that during this time the consumption of fluoroquinolones in Canada increased markedly with total fluoroquinolone use up by 84.3%. When this was investigated further it was noted that the newer fluoroquinolones had contributed greatly to this increase with the use of levofloxacin, gatifloxacin and moxifloxacin increasing by 12,300% compared to a 22.4% increase in ciprofloxacin use over the same time. Using resistance data from the Canadian Respiratory Organism Surveillance Study (CROSS) database, it was demonstrated that during the entire six-year period resistance to the new fluoroquinolones remained at approximately 1% (Table 2). Therefore although the consumption of new fluoroquinolones has increased greatly in Canada the rate of resistance to these agents among S. pneumoniae remains low.
Further data from the CROSS database was reported by L. Palatnik and co-workers who provided an overview of the antibiotic susceptibility of 19,334 RTI pathogens collected during this same six-year period (1997-2003). The researchers noted that globally, RTIs are a major cause of morbidity and mortality, with four main pathogens involved in over 50% of bacteriologically proven RTIs, S. pneumoniae, H. influenzae, M. catarrhalis and Streptococcus pyogenes. There has been concern that the empiric management of these infections is being weakened by increasing rates of antimicrobial resistance particularly in S. pneumoniae, which has been reported to be associated with treatment failures. This has led to the need for continual surveillance of the activity of available agents. In the CROSS analysis, susceptibility testing against 25 antibiotics was performed using the NCCLS-approved broth micro-dilution method. The authors reported that the prevalence of penicillin non-susceptible S. pneumoniae was 21%, erythromycin-resistant S. pneumoniae was 9.2% and levofloxacin-resistant pneumococcus was 1.0%. In regard to H. influenzae, 21.4% were -lactamase producers, while the corresponding rate for M. catarrhalis was almost universal, at 92.4%. There were no penicillin-resistant Group A Streptococcus isolates identified, although 5.2% were erythromycin-resistant. These results support the continued efficacy of levofloxacin and new fluoroquinolones, although continued care must be taken to ensure that these important agents are used judiciously in order to avoid the development of future resistance.
These results were supported by the latest data available from the Global Landscape on the Bactericidal Activity of Levofloxacin (GLOBAL) program, which is a worldwide surveillance initiative tracking changes in resistance among common pathogens as they occur. Such data is becoming of increasing clinical importance with the advent of SARS, and recognition of increasing resistance, particularly to -lactams, macrolides and TMP-SMX, which is associated with clinical failure. The data reported covered the 1999-2003 period using isolates from 11 countries, which were centrally tested against penicillin, azithromycin, levofloxacin, ampicillin and comparator agents. Results confirmed that the largest increase in penicillin resistance among the pneumococcus occurred in China, increasing from 10 to 26% and in South Africa from 8 to 15%. Azithromycin resistance increased in France, Germany, Italy, South Africa and Thailand and was greater than 45% in China, France, Hong Kong, Italy, South Korea and Thailand (Table 3). In addition, the rates of multidrug-resistant S. pneumoniae ranged from 1.1% in Germany to a staggering 42.2% in South Korea (Table 4). Levofloxacin was shown to maintain excellent activity against all S. pneumoniae with an overall worldwide resistance rate of 0.9%. Levofloxacin was also extremely active against H. influenzae and M. catarrhalis.


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Table 2. Relationship between fluoroquinolone use and Streptococcus pneumoniae resistance (Canada 1997-2003)
Table 2

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Table 3. Percent resistance of Streptococcus pneumoniae isolates collected during 1999-2000, 2001-2002 and 2003
Table 3

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Table 4. Changes in multidrug resistance among Streptococcus pneumoniae collected in 1999-2000, 2001-2002, and 2003
Table 4
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Ciprofloxacin but not levofloxacin selects for mutational resistance

An important pharmacologic study presented at ICAAC by M. Miller, N. Jumbe, G. Drusano and colleagues found that pump over-expression may play an important role in the development of resistance in S. pneumoniae. Using mouse studies and human equivalent doses of fluoroquinolones, it was demonstrated that ciprofloxacin, but not levofloxacin, selected for an efflux pump mutant. When infected mice were treated with ciprofloxacin resistance due to pmrA mutations developed, but this did not happen with levofloxacin. Once ciprofloxacin selected the first pump mutation, which was associated with over-expression of the efflux pump, secondary mutations in parC were selected with both ciprofloxacin and levofloxacin. This supports the view that hydrophilic fluoroquinolones such as ciprofloxacin are more likely to be associated with pump overexpression resulting in a greater likelihood of secondary mutations causing high-level resistance that is ultimately associated with clinical failure.

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Enhanced penetration of high-dose levofloxacin in critically ill patients

Legionella pneumophila is becoming increasingly recognized as an important RTI pathogen, and is associated with significant morbidity and mortality. Recent research has shown that the pathogenesis of Legionella infections involves an apoptotic process and the effects of antimicrobials on bacterial counts in a murine infection were analyzed. Dr. C. Nara, Toho University School of Medicine, and colleagues reported that after intratracheally infecting mice with L. pneumophila, increasing doses of ampicillin, minocycline, clarithromycin or levofloxacin were administered through a gastric tube from day one for three days. A dose-dependent improvement in survival was noted in the mice treated with levofloxacin, minocycline and clarithromycin but not for ampicillin. When compared to the control group with a 15% survival, levofloxacin and clarithromycin were associated with a 100% survival and minocycline with a 62% survival rate. A difference in effect was noted between the antibiotics in terms of bacterial clearance and suppression of apoptosis on day four. Bacterial numbers were reduced by 1.2 log for levofloxacin, 1.1 log for minocycline and 0.4 log for clarithromycin. The percent suppression of apoptosis was 86.5% for levofloxacin, 66.2% for clarithromycin and 46.8% for minocycline. The researchers concluded that these results demonstrate that while levofloxacin, minocycline and clarithromycin are effective agents for treating L. pneumophila infection, levofloxacin may be the preferred agent because it also possesses ability to suppress apoptosis, which the other two agents do not have to such a marked degree.

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Renal role for levofloxacin

Results from a study investigating the penetration of levofloxacin into renal cysts in a patient with autosomal dominant polycystic kidney disease (ADPKD) and Group B Streptococcus infection were reported by L. Miller, UCLA Medical Center. Treatment of cyst infection in patients with this kidney disease can be very problematic with many antibiotics having poor ability to penetrate into the cyst. Making treatment more difficult is the problem that -lactams and aminoglycosides do not penetrate into the cyst very well, and also the increasing incidence of resistance among uropathogens limits the utility of other agents commonly used in the past. Therefore fluoroquinolones have been advocated for treatment in this group of patients but until now there has been no data of the penetration of the newer fluoroquinolones into renal cysts. In this study, a patient with ADPKD and bacteremia due to Group B Streptococcus, resistant to TMP-SMX, was shown to achieve a serum/cyst ratio of 96% following administration of levofloxacin. In contrast a serum/cyst ratio of less than 40% was achieved following ampicillin administration (Table 5). The clinical outcome improved following antibiotic therapy with these two agents. The researchers concluded that levofloxacin penetrated extremely well into renal cysts and may be useful for treating infections in patients with ADPKD, especially for Gram-positive pathogens.


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Table 5. Antibiotic levels in serum and cyst. Synchronous antibiotic concentrations from cyst and serum performed after levofloxacin and ampicillin administered two and six hours prior to sampling, respectively.
Table 5
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Levofloxacin: effective strategy against bioterrorism

With international focus on the problems of bioterrorism it was very timely to have a report from H. Heine et al., US Army Medical Research Institute of Infectious Diseases (USAMRIID) on the evaluation of levofloxacin in a mouse model of inhalational challenge Bacillus anthracis. To determine doses and schedules of treatment, levofloxacin was administered intraperitoneally to BALB/c mice 24 hours after an aerosol anthrax challenge. Treatment continued for 21 days. Levofloxacin was administered in three different schedules (once daily, twice daily and four times a day). Blood was collected at 30 minutes, 1, 2, 4, and 6 hours after dosing. Population modeling was performed and levofloxacin exhibited good activity against the spore challenge, and schedule of administration was highly significant (p < 0.000001) and affected time to death (p < 0.0001). The AUC/MIC ratio was significant when comparing the twice-daily and four-times-daily groups, with an AUC/MIC ratio breakpoint of 132 identified as probable for a good outcome. This paper demonstrated that levofloxacin was highly active against B. anthracis in the mouse model, and would probably be an effective treatment for this infection in humans.

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