Beneficial Effects of Protein Synthesis-inhibiting Antibiotics in Bacterial Pneumonia
Beneficial Effects of Protein Synthesis-inhibiting Antibiotics in Bacterial Pneumonia
Abstract & Commentary
By Dean L. Winslow, MD, FACP, FIDSA, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center; Clinical Professor, Stanford University, School of Medicine, Section Editor, HIV, is Associate Editor for Infectious Disease Alert.
Dr. Winslow serves as a consultant for Siemens Diagnostics, and is on the speaker's bureau for Boehringer-Ingelheim and GSK.
Synopsis: Mice infected with influenza virus and superinfected with S. pneumoniae were treated with ampicillin, clindamycin, or azithromycin. Survival was lowest with ampicillin (56%) and best with either clindamycin alone (82%), ampicillin plus clindamycin (80%), or azithromycin (92%).
Source: Karlstrom A, et al. Treatment with protein synthesis inhibitors improves outcomes of secondary bacterial pneumonia after influenza. J Infect Dis. 2009;199:311-319.
Balb/CJ mice infected with influenza virus were superinfected with an antibiotic-susceptible strain of S. pneumoniae and treated intraperitoneally with ampicillin alone, clindamycin alone, ampicillin plus clindamycin, or azithromycin. Survival was assessed, histopathologic examination of the lungs was performed at necropsy, and TNF-alpha levels expressed by macrophages were measured. Improved survival in mice treated with either clindamycin or azithromycin appeared to be mediated by decreased inflammation reflected by lower levels of inflammatory cells and pro-inflammatory cytokines in the lungs and less severe histopathologic findings.
Commentary:
While covering the Pediatric ICU on ID consult service recently at our county hospital, the PICU team presented to me the case of a previously healthy 13-year-old girl who developed a severe multilobar pneumonia due to methicillin-resistant S. aureus likely following influenza. Fortunately, she survived despite requiring mechanical ventilation with a high-frequency ventilator and the use of vasopressors. Despite the availability of potent antibiotics, pneumonia remains a major cause of death in both the developed and the developing world, and optimum antimicrobial therapy for most patients with bacterial pneumonia remains uncertain. While this paper describes in vivo experimental data, the results are intriguing from a mechanistic standpoint, and dovetail with some preliminary observations that suggest that antibiotics (such as the macrolides, linezolid, clindamycin, the tetracyclines, and rifampin) have potentially beneficial effects independent of their antimicrobial activity.
The possible clinical benefit of adding either clindamycin or linezolid to cell wall-active antibiotics in the treatment of toxic shock syndrome due to either Group A streptococcus or S. aureus is widely accepted. This beneficial effect has been attributed to the effects of these antibiotics on inhibiting bacterial toxin production. However, an intriguing paper was recently published which described data from a retrospective study of patients with severe sepsis due to pneumonia. In this study, macrolide use was associated with decreased mortality in these patients despite the fact that the patients were infected with macrolide-resistant pathogens, strongly supporting an anti-inflammatory effect of these agents independent of antimicrobial activity.1 Another experimental study supporting the direct anti-inflammatory effect of a macrolide antibiotic utilized a rat model of E. coli sepsis. Despite having no antimicrobial activity vs. the challenge strain of E. coli used, clarithromycin reduced lethality of infection vs. control and reduced plasma levels of endotoxin and TNF-alpha.2
While the above data are fascinating and almost certainly have clinical relevance, caution needs to be exercised by clinicians. These bacteriostatic/protein synthesis-inhibiting antimicrobials should be used with discernment. It is important that the hypotheses generated by studies like these be tested in prospective, randomized, controlled trials. One of my "pet peeves" is the widespread addition of rifampin to cell wall-active antibiotics in the treatment of S. aureus infections despite lack of well-controlled clinical trial data to support this practice. This has never made sense to me, at least in patients with staphylococcal endocarditis, since rifampin is known to cause in vitro antagonism of the bactericidal activity of cell wall-active agents and we know that bactericidal activity is important for cure of endocarditis due to the relative impermeability to neutrophils of the vegetation's fibrin/platelet matrix. A recent retrospective study closely examined this practice at one institution and found that addition of rifampin resulted in delayed clearance of bacteremia (5.2 vs. 2.1 days), frequent development of rifampin resistance (in 56% of cases), reduced survival (79% vs. 95%), hepatotoxicity, and serious drug-drug interactions.3 Until better data are available, the use of adjunctive macrolides, linezolid, clindamycin, and rifampin should also be used with caution in patients with known or suspected bacterial meningitis since antagonism could potentially have deleterious consequences due to the impaired opsonization which is present in the cerebrospinal fluid.
References:
- Restrepo MI, et al. Impact of macrolide therapy on mortality for patients with severe sepsis due to pneumonia. Eur Respir J. 2009;33:153-159.
- Cirioni O, et al. Efficacy of the combination of tachyplesin III and clarithromycin in rat models of Escherichia coli sepsis. Antimicrob Agents Chemother. 2008;52:4351-4355.
- Riedel DJ, et al. Addition of rifampin to standard therapy for treatment of native valve infective endocarditis caused by Staphylococcus aureus. Antimicrob Agents Chemother. 2008;52:2463-2467.
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