Antibacterial activities of erythromycins A, B, C, and D and some of their derivatives

Kibwage, IO; Hoogmartens, Jos; Roets, Eugène; Vanderhaeghe, Hubert; Verbist, Ludo; Dubost, M; Pascal, C.; Petitjean, Patrice; Levol, G.

doi:10.1128/aac.28.5.630

Cited by 38 publications

(36 citation statements)

References 13 publications

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“…BAL was performed with a total volume of 1 ml PBS containing 0.1 mM EDTA. When required, red blood cells were removed by resuspending the BAL fluid cells in 100 l of lysis buffer (150 mM NH 4 Cl, 10 mM KHCO 3 , 0.1 mM EDTA [pH 7.2]) for 2 min at room temperature, followed by washing in 1 ml PBS. The total number of cells was then counted and adjusted to cells per milliliter of BAL fluid.…”

Section: Methodsmentioning

confidence: 99%

“…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)(5)(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.…”

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confidence: 99%

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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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Section: Methodsmentioning

confidence: 99%

mentioning

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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“…2 Erythromycin A (EA) is the main component, but during fermentation several related substances such as erythromycins B (EB), C (EC), D (ED), E (EE), F (EF), A N-oxide (EANO) and N-demethylerythromycin A (NdMeEA) are formed in small amounts. Figure 1 shows the chemical structures.…”

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confidence: 99%

Investigation of unknown related substances in commercial erythromycin samples with liquid chromatography/mass spectrometry

Govaerts

Chepkwony

Schepdael

et al. 2000

Rapid Commun. Mass Spectrom.

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A selective reversed phase liquid chromatography/mass spectrometry (LC/MS(n)) method is described for the identification of erythromycin impurities and related substances in commercial erythromycin samples. Mass spectral data are acquired on a LCQ ion trap mass spectrometer equipped with an electrospray interface operated in positive ion mode. The LCQ is ideally suited for identification of impurities and related substances because it provides on-line LC/MS(n) capability. Compared with UV detection, this hyphenated LC/MS(n) technique provides as a main advantage efficient identification of novel substances without time-consuming isolation and purification procedures. Using this method four novel related substances were identified in commercial samples.

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“…AHE is microbiologically inactive but inhibits drug oxidation in the liver and thus is considered to be an important factor for the unwanted drug-drug interactions of erythromycin (20,36). In vitro AHE is a more potent inhibitor of the cytochrome P450 3A subfamily than erythromycin, thereby prolonging elimination of benzodiazepines, immunosuppressants, statins, and many more drugs (36).…”

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confidence: 99%

Blood, Tissue, and Intracellular Concentrations of Erythromycin and Its Metabolite Anhydroerythromycin during and after Therapy

Krasniqi

Matzneller

Kinzig

et al. 2012

Antimicrob Agents Chemother

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For macrolides, clinical activity but also the development of bacterial resistance has been attributed to prolonged therapeutic and subtherapeutic concentrations. Although erythromycin is a long-established antimicrobial, concomitant determination of the pharmacokinetics of erythromycin and its metabolites in different compartments is limited. To better characterize the pharmacokinetics of erythromycin and its anhydrometabolite (anhydroerythromycin [AHE]) in different compartments during and after the end of treatment with 500 mg of erythromycin four times daily, concentration-time profiles were determined in plasma, interstitial space of muscle and subcutaneous adipose tissue, and white blood cells (WBCs) at days 1 and 3 of treatment and 2 and 7 days after end of therapy. In WBCs, concentrations of erythromycin exceeded those in plasma approximately 40-fold, while free concentrations in plasma and tissue were comparable. The observed delay of peak concentrations in tissue might be caused by fast initial cellular uptake. Two days after the end of treatment, subinhibitory concentrations were observed in plasma and interstitial space of both soft tissues, while 7 days after the end of treatment, erythromycin was not detectable in any compartment. This relatively short period of subinhibitory concentrations may be advantageous compared to other macrolides. The ratio of erythromycin over AHE on day 1 was highest in plasma (2.81 ؎ 3.45) and lowest in WBCs (0.27 ؎ 0.22). While the ratio remained constant between single dose and steady state, after the end of treatment the concentration of AHE declined more slowly than that of the parent compound, indicating the importance of the metabolite for the prolonged drug interaction of erythromycin. Macrolides account for 10 to 15% of the worldwide consumption of antibiotics (25,31). Although in many countries erythromycin has been replaced by newer relatives like azithromycin and clarithromycin, prescription of erythromycin still has a substantial place in less developed countries but also certain regions within Europe (15, 40). However, bacterial resistance against macrolides dramatically escalated in many countries during the last decades (14,23,35). Total consumption of antimicrobials on the one hand and the presence of long periods of exposure of bacterial populations to subinhibitory concentrations of antibiotics on the other hand are considered critical factors for selecting bacterial resistance (2, 3, 16).Erythromycin is known for its highly variable bioavailability after oral ingestion and its susceptibility toward degradation under acidic conditions. Although its half-life in plasma is short and the pharmacokinetic (PK) profile intraindividually heterogeneous, it is very well distributed throughout body tissues and accumulates in leukocytes (11). While clinical studies have shown the effectiveness of erythromycin in skin and soft tissue infections (33, 39), the in vivo penetration and the resulting free concentrations in interstitial space of soft tissues, i.e., the ...

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Antibacterial activities of erythromycins A, B, C, and D and some of their derivatives

Cited by 38 publications

References 13 publications

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

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

Investigation of unknown related substances in commercial erythromycin samples with liquid chromatography/mass spectrometry

Blood, Tissue, and Intracellular Concentrations of Erythromycin and Its Metabolite Anhydroerythromycin during and after Therapy

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