Immunomodulatory Clarithromycin Treatment of Experimental Sepsis and Acute Pyelonephritis Caused by Multidrug-Resistant
            <i>Pseudomonas aeruginosa</i>

Giamarellos‐Bourboulis, Evangelos J.; Adamis, Theodoros; Laoutaris, George; Sabracos, Lambros; Koussoulas, Vassilios; Mouktaroudi, Maria; Perrea, Despina; Karayannacos, Panayotis E.; Giamarellou, Helen

doi:10.1128/aac.48.1.93-99.2004

Cited by 83 publications

(92 citation statements)

References 27 publications

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“…Intravenous clarithromycin in the therapeutic range improved survival in a murine model of sepsis caused by susceptible E. coli, multidrug-resistant P. aeruginosa, or pandrug-resistant Klebsiella pneumoniae, and this was associated with decreased serum TNF-␣ and reactive oxygen species (78,80,81). These pathogens were not susceptible to clarithromycin in vitro, and the effects were observed even if clarithromycin was administered after the animals developed sepsis-associated pulmonary edema.…”

Section: Influenza and Sepsismentioning

confidence: 97%

Mechanisms of Action and Clinical Application of Macrolides as Immunomodulatory Medications

2010

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SUMMARY Macrolides have diverse biological activities and an ability to modulate inflammation and immunity in eukaryotes without affecting homeostatic immunity. These properties have led to their long-term use in treating neutrophil-dominated inflammation in diffuse panbronchiolitis, bronchiectasis, rhinosinusitis, and cystic fibrosis. These immunomodulatory activities appear to be polymodal, but evidence suggests that many of these effects are due to inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and nuclear factor kappa B (NF-κB) activation. Macrolides accumulate within cells, suggesting that they may associate with receptors or carriers responsible for the regulation of cell cycle and immunity. A concern is that long-term use of macrolides increases the emergence of antimicrobial resistance. Nonantimicrobial macrolides are now in development as potential immunomodulatory therapies.

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Section: Influenza and Sepsismentioning

confidence: 97%

Mechanisms of Action and Clinical Application of Macrolides as Immunomodulatory Medications

2010

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“…The study was retrospective, and there was much heterogeneity regarding the antibiotics used against P. aeruginosa. In support of using macrolides when treating severe Gram-negative infections, a rabbit model of pyelonephritis caused by multidrugresistant P. aeruginosa showed increased survival after coadministration of the macrolide clarithromycin and the aminoglycoside amikacin, which was probably attributable to the immunomodulatory properties of clarithromycin, as reflected by decreased levels of TNF-␣ (45).…”

Section: Figmentioning

confidence: 99%

The Nonantibiotic Macrolide EM703 Improves Survival in a Model of Quinolone-Treated Pseudomonas aeruginosa Airway Infection

Kasetty

Bhongir

Papareddy

et al. 2017

Antimicrob Agents Chemother

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Macrolide antibiotics are used as anti-inflammatory agents, e.g., for prevention of exacerbations in chronic obstructive pulmonary disease and cystic fibrosis. Several studies have shown improved outcomes after the addition of macrolides to ␤-lactam antibiotics for treatment of severe community-acquired pneumonia. However, a beneficial effect of macrolides in treating Gram-negative bacterial airway infections, e.g., those caused by Pseudomonas aeruginosa, remains to be shown. Macrolide antibiotics have significant side effects, in particular, motility-stimulating activity in the gastrointestinal tract and promotion of bacterial resistance. In this study, EM703, a modified macrolide lacking antibiotic and motility-stimulating activities but with retained anti-inflammatory properties, was used as an adjunct treatment for experimental P. aeruginosa lung infection, in combination with a conventional antibiotic. Airway infections in BALB/cJRj mice were induced by nasal instillation of P. aeruginosa; this was followed by treatment with the quinolone levofloxacin in the absence or presence of EM703. Survival, inflammatory responses, and cellular influx to the airways were monitored. Both pretreatment and simultaneous administration of EM703 dramatically improved survival in levofloxacin-treated mice with P. aeruginosa airway infections. In addition, EM703 reduced the levels of proinflammatory cytokines, increased the numbers of leukocytes in bronchoalveolar lavage fluid, and reduced the numbers of neutrophils present in lung tissue. In summary, the findings of this study show that the immunomodulatory properties of the modified macrolide EM703 can be important when treating Gram-negative pneumonia, as exemplified by P. aeruginosa infection in this study.KEYWORDS macrolide, EM703, host defense, anti-inflammatory, Pseudomonas aeruginosa M acrolide antibiotics (for example, erythromycin, azithromycin, and clarithromycin) have caught interest for use in the treatment of chronic airway inflammation (1). Reduction of pulmonary exacerbations has been demonstrated in cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) (2, 3). Macrolides display broad biological responses, including bacteriostatic activity, stimulation of gastrointestinal motility, and anti-inflammatory properties (4-6). Each of these effects could be advantageous, depending on the clinical context; however, promotion of drug-resistant bacteria and diarrhea limit the clinical use of macrolides as anti-inflammatory agents.In severe community-acquired pneumonia, which is often caused by the Grampositive coccus Streptococcus pneumoniae, meta-analyses have shown that the addition of a macrolide antibiotic to a ␤-lactam has beneficial effects, reducing mortality rates (7-9). Pneumonia caused by Gram-negative bacteria, in particular, Pseudomonas aerugi-

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“…Recent studies suggest that macrolides may have beneficial effects for patients at risk from certain infections, due to their immunomodulatory effects rather than their antimicrobial properties [7]. These immunomodulatory effects are supported by the clinical success observed in noninfectious, but immune-related, conditions, including asthma [8], chronic obstructive pulmonary disease (COPD) [9], diffuse panbronchiolitis [10] and bronchiectasis [10].…”

mentioning

confidence: 99%

Impact of macrolide therapy on mortality for patients with severe sepsis due to pneumonia

Restrepo¹,

Mortensen²,

Waterer³

et al. 2009

European Respiratory Journal

175

112

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Recent studies suggest that macrolides may have beneficial effects for patients at risk for certain infections. The current authors examined the effect of macrolide therapy on 30-and 90-day mortality for patients with severe sepsis caused by pneumonia.A retrospective cohort study was conducted at two tertiary teaching hospitals. Eligible subjects were admitted with a diagnosis of, had chest radiography consistent with, and had a discharge diagnosis of pneumonia and clinical criteria of severe sepsis. Subjects were considered to be on macrolides if they received at least one dose within 48 h of admission.Severe sepsis was present in 237 (30.1%) subjects, out of whom 104 (43.9%) received macrolides. Mortality was 20.3% at 30 days and 24.5% at 90 days. In the multivariable analysis, the use of macrolide was associated with decreased mortality at 30 days (hazard ratio (HR) 0.3, 95% confidence interval (CI) 0.2-0.7) and at 90 days (HR 0.3, 95% CI 0.2-0.6) in patients with severe sepsis and in patients with macrolide-resistant pathogens (HR 0.1, 95% CI 0.02-0.5).Macrolide use was associated with decreased mortality in patients with severe sepsis due to pneumonia and macrolide-resistant pathogens. Confirmatory studies are needed to determine whether macrolide therapy may be protective for patients with sepsis.

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Immunomodulatory Clarithromycin Treatment of Experimental Sepsis and Acute Pyelonephritis Caused by Multidrug-Resistant Pseudomonas aeruginosa

Cited by 83 publications

References 27 publications

Mechanisms of Action and Clinical Application of Macrolides as Immunomodulatory Medications

Mechanisms of Action and Clinical Application of Macrolides as Immunomodulatory Medications

The Nonantibiotic Macrolide EM703 Improves Survival in a Model of Quinolone-Treated Pseudomonas aeruginosa Airway Infection

Impact of macrolide therapy on mortality for patients with severe sepsis due to pneumonia

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