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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 20th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID)

Vienna, Austria / April 10-13, 2010

Community-acquired pneumonia (CAP) is not a new entity but as Dr. Roger Finch, Nottingham University Hospitals NHS Trust, UK, pointed out, “There are always new issues, new problems, new ways of thinking, new ways of managing our patients.” With pneumococcal pneumonia, mortality is around 10% to 12%, a figure that has not changed very much over the last 30 to 40 years, despite the availability of new agents. Streptococcus pneumoniae is the most common pathogen in CAP, both in the outpatient setting and in hospitalized patients (regardless of whether they are in the intensive care unit with severe disease or on the ward).

According to the American Thoracic Society/Infectious Diseases Society of American (ATS/IDSA) guidelines for treatment of non-severe CAP, respiratory fluoroquinolones are preferred. In patients in the ICU with no risk factors for methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa, the preferred agents are either b-lactams with azithromycin or respiratory fluoroquinolones. Confirmed Dr. Finch, “Fluoroquinolones are very much embedded in the practice of managing CAP.”

The Emergence of Resistance

Despite emerging resistance, there are fewer new agents being approved, noted Dr. Donald Low, Mount Sinai Hospital, Toronto, Ontario. Surveillance programs in some European countries have found resistance to penicillin in the range of 25% to 50%. Similar figures have been reported for macrolides, and “there is evidence that macrolide resistance, whether high or low, is important for patient outcomes,” stated Dr. Low.

The situation in Canada was reflected in a poster (P1676) from the Canadian Bacterial Surveillance Network (CBSN). Between 1993 and 2007, resistance to erythromycin increased from 1.9% to 22.4%. Penicillin resistance (using a breakpoint of =2 µg/mL) increased somewhat less dramatically from 0.9% in 1993 to 8.3% in 2009. Discussant Dr. Karen Green, Mount Sinai Hospital, concluded, “In Canada, pneumococcal resistance to b-lactam antibiotics…and macrolides continues to rise.”

This is in contrast to resistance to the respiratory fluoroquinolones. In his review of data from the same surveillance program, Dr. Low explained, “Over the last decade, we have seen resistance rates to moxifloxacin and levofloxacin remain relatively stable, and you might even say there is a decrease, with resistance rates <5%.”

The widespread vaccination programs for infants and young children with the conjugate 7-valent pneumococcal vaccine (PCV7) from 2000 onwards have undoubtedly helped contain resistance in pneumococcal infections. Although this vaccine only covers seven of over 90 serotypes of S. pneumoniae, the serotypes that are covered account for a large proportion of the multidrug-resistant strains. “This has been a real success story,” commented Dr. Low, “but there is a downside… and that is we are seeing serotype replacement.” This is a cause for concern for clinicians, given that these new serotypes, such as serotype 19A, are also multidrug-resistant.

Fluoroquinolone Properties

In the view of Dr. Low, fluoroquinolones have retained their high activity in part because of their pharmacokinetic and pharmacodynamic properties. To be effective, concentrations need to be as high above the minimum inhibitory concentration (MIC) for as long as possible; that is, the area under the curve (AUC) should be as high as possible with respect to the MIC. A study with levofloxacin showed that if a good AUC:MIC ratio can be achieved, not only will success rates be higher, but eradication is also more likely (JAMA 1998;279(2):125-9). Indeed, for AUC:MIC >100, the microbiological success rate was 100%. For moxifloxacin, the other widely available respiratory fluoroquinolone, the AUC:MIC ratio is 384 (Clin Infect Dis 2003;37(9):1210-5). With such high eradication rates, it is difficult for bacteria to develop resistance.

A closer look at the mechanism of action of the fluoroquinolones shows that these drugs target enzymes essential for DNA replication, namely topoisomerase IV (ParC) and DNA gyrase (GyrA). “While the older fluoroquinolones preferentially bind to one of the two targets, moxifloxacin binds almost equally to both targets,” explained Dr. Low. “It is almost like having two drugs.” This then could explain why, although fluoroquinolone resistance remains low in general, it appears particularly low for moxifloxacin (<1%). And when resistance to moxifloxacin is observed, it is often in patients with prior exposure to other fluoroquinolones.

It is also interesting to note that in the past, levofloxacin was generally used at a dose of 400 mg, but currently a dose of 500 mg is usually recommended. The lower dose may not have achieved sufficiently high AUC:MIC ratios for effective eradication, perhaps providing an indication why resistance to levofloxacin—while low (<5% in Canada)—is not as low as moxifloxacin. Dr. Low concluded, “We want to use the right antibiotic at the right dose and for the right duration, and so hopefully we can treat patients effectively and also slow down the emergence of resistance.”

Appropriate Use

Although the guidelines do not recommend fluoroquinolones in all patients (for example, where there is a risk of MRSA), with careful patient selection, they can be extremely useful agents. For example, they have good penetration into lung tissue, high bioavailability and an oral formulation (allowing an early switch to oral therapy in severely ill patients initially receiving intravenous antibiotics).

There have been two main studies comparing the fluoroquinolones moxifloxacin and levofloxacin. In the Community-Acquired Pneumonia Recovery in the Elderly (CAPRIE) study, 401 patients over 65 years hospitalized for CAP were randomized to one or the other agent (Clin Infect Dis 2006;42(1):73-81). The primary end point was cardiac safety, and no difference was observed. “What was interesting, though, is the speed of resolution,” reported Dr. Thomas File, Head, Infectious Diseases Section, Summa Health System, Akron, Ohio, “as all our patients want to get better quickly.” The data showed that significantly more patients treated with moxifloxacin achieved clinical recovery in 3 to 5 days (98%) compared to those treated with levofloxacin (90%) (P=0.01). In general, both drugs were well tolerated, and there were no significant differences in terms of adverse events reported. “Interestingly, of the patients who developed Clostridium difficile infection, 6 out of 7 were in the levofloxacin arm; this was not significant but I think it is an interesting observation,” Dr. File remarked to delegates.

In the MOTIV (Moxifloxacin Treatment IV) study, very ill patients (pneumonia severity index of at least 3) were randomized to moxifloxacin or levofloxacin plus ceftriaxone (Clin Infect Dis 2008;46(10):1499-509). No differences were found in the primary efficacy outcome (clinical response rate at test of cure). Concluded Dr. File, “Monotherapy with moxifloxacin was not inferior to combination therapy.”

Summary

The emergence of antibiotic resistance is a major concern at present, particularly in the management of potentially serious infections such as CAP. Vaccinations and judicious antibiotic use—that is, administering antimicrobials only when necessary and selecting the right antibiotic with potent activity against the target organism—should help keep antibiotic resistance under control. Fluoroquinolones are an important drug class for treating CAP, and current indications are that antimicrobial resistance to these agents is low, particularly in the case of moxifloxacin.