Something New for Community-Acquired Pneumonia?

To the Editor—Increasing macrolide resistance among respiratory pathogens, particularly Streptococcus pneumoniae and Mycoplasma pneumoniae, may be an indication that the role of macrolides as monotherapy agents in community acquired bacterial pneumonia (CABP) may be diminishing. Community-acquired pneumonia (CAP) continues to be associated with significant morbidity, mortality, and economic burden. In North America approximately 80% of such cases are treated as outpatients, and national guidelines from the United States have advocated monotherapy with a macrolide for such outpatients without comorbidity or recent antibiotic treatment [1]. For those with comorbidity, in areas of increased pneumococcal resistance and for inpatients, it was felt that broader coverage was necessary. Data from many countries show an increased prevalence of macrolide-resistant S. pneumoniae. However, resistance does not automatically mean treatment failure. It is important to also differentiate among cases associated with erm(B)-mediated resistance (high level) vs those with mef (A) resistance (low level). Retrospective data show a positive correlation among macrolide resistance rates ≥25%, treatment failure, and costs [2]. Increased mortality in cases of CABP failing initial outpatient macrolide therapy was reported even with low-level macrolide resistance [3]. In the United States the rate of macrolide-resistant S. pneumoniae overall is near 50% [4]. The Infectious Diseases Society of America and American Thoracic Society guidelines recommend that a macrolide not be used as monotherapy in regions with a high rate of high-level macrolide-resistant S. pneumoniae. In such cases, use of alternate regimens such as a respiratory fluoroquinolone or a beta lactam plus a macrolide should be considered. The study by File et al in Clinical Infectious Diseases used a standard experimental design and fulfills the criteria set forth by the US Food and Drug Administration for the study of drugs in CABP [5]. The study is a follow-up to a recent phase 3 study of oral solithromycin vs oral moxifloxacin for treatment of CABP [6]. Noninferiority of solithromycin to moxifloxacin was achieved in early clinical response in the intention-to-treat (ITT) group. In terms of adverse outcomes, there was a higher incidence of infusion-related events in the solithromycin arm, but otherwise no significant differences were noted regarding QT prolongation, Clostridium difficile infection, and abnormal liver function tests. The study was well written with a number of strengths and some weaknesses. Adding to the robustness of the study is the large sample size (863 patients) in 141 centers around the globe, thereby adding to the generalizability of the results. Importantly, the main microbiological studies were carried out at a central laboratory, and pathogens were found in 37.8% of patients. Weaknesses include the fact that almost one quarter of the patients were pneumonia severity index (PSI) 2 and less than 1% were PSI 5. This is reflected in the low mortality rates of 1.2% and 1.6% in the solicthromycin and moxifloxacin arms, respectively. Also, drugs that might have adversely interacted with the study antibiotics, particularly regarding QT prolongation, were excluded. The increasing awareness of respiratory viruses as potential pathogens or copathogens, in CAP not withstanding, the pneumococcus, and atypicals such as M. pneumoniae remain priority targets. Despite some debate regarding North American and certain European guidelines relating to the role of atypical pathogens, particularly in outpatients, this study supports such a role and the treatment of atypicals since more than 30% of organisms in each microbiological ITT arm were either Mycoplasma or Legionella species. Among pneumococcal isolates resistant to macrolides, the response rates for solithromycin and moxifloxacin at early clinical response were 83% (10/12) and 71% (10/14) of patients, respectively. If monotherapy with a macrolide is no longer an option, fluoroquinolones alone or a combination of a beta lactam plus macrolide become choices. Increasing doxycycline resistance makes this drug less appealing. The fluoroquinolones are generally excellent antibiotics but are often misused and can be associated with adverse outcomes such as C. difficile enterocolitis and tendinopathy. The combination regimen is logistically more difficult to use and less likely to be fully complied with by the patient. Solithromycin, an advanced macrolide, offers the potential of reliable monotherapy once again. It has 3 instead of only 1 ribosomal binding site and is effective against key respiratory pathogens including those that are macrolide resistant. It also has antiinflammatory activity that may help to mitigate damage resulting from the host inflammatory response. This drug appears effective in the treatment of CABP and is a promising new agent. To date, there is nothing to suggest any unusual or unexpected adverse events. However, as we have learned from other drugs, decisions regarding safety often require much larger sample sizes than are supplied by registration trials alone. Potential conflict of interest. The author is part of a data safety review board with Bayer and Merck and is on an advising board for Cempra. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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