The activity of clarithromycin and its 14-hydroxy metabolite against Haemophilus influenzae, determined by in-vitro and serum bactericidal tests

Dabernat, H.; Delmas, Catherine; Seguy, M; Fourtillan, J. B.; Girault, Jean‐Pierre; Lareng, M.B.

doi:10.1093/jac/27.suppl_a.19

Cited by 43 publications

(16 citation statements)

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“…In a murine model of H. influenzae infection, the 14-OH-clarithromycin metabolite was found to be effective [23]. Some workers have suggested in vitro synergy of clarithromycin and 14-OH-clarithromycin against H. influenzae [3,24), although the relatively low levels of 14-OH in ELF and mucosa in our study may not support this occurrence in vivo. The low MIC 90 (0.03 mg·l -1 ) of clarithromycin against Mycoplasma pneumoniae [25] and against Legionella pneumophila (MIC 90 , 0.12 mg·l -1 ) [26] suggest high efficacy in these atypical pneumonias.…”

Section: Discussioncontrasting

confidence: 86%

The levels of clarithromycin and its 14-hydroxy metabolite in the lung

Honeybourne¹,

Kees²,

Andrews³

et al. 1994

Eur Respir J

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T Th he e l le ev ve el ls s o of f c cl la ar ri it th hr ro om my yc ci in n a an nd d i it ts s 1 14 4--h hy yd dr ro ox xy y m me et ta ab bo ol li it te e i in n t th he e l lu un ng g ABSTRACT: Clarithromycin is a new macrolide that has a longer half-life than erythromycin and is claimed to reach higher tissue concentrations. We aimed to investigate whether, following oral administration, the drug and its 14-hydroxy metabolite reach levels in lung tissue that are likely to be clinically effective against common respiratory pathogens. Ten patients undergoing diagnostic bronchoscopy received seven doses of clarithromycin, 500 mg b.i.d. orally. Bronchoscopy was performed at a mean time of 4.25 h after the last dose. At bronchoscopy, bronchial biopsies and bronchoalveolar lavage were performed. Clarithromycin and its 14-OH metabolite were measured in serum, bronchial biopsies, epithelial lining fluid (ELF) and alveolar cells.Mean levels of clarithromycin were 4.0 mg·l -1 in serum, 16.8 mg·kg in bronchial biopsies, 20.5 mg·l -1 in ELF and 372.7 mg·l -1 in alveolar cells. The equivalent levels of 14-OH metabolite were 0.7, 2.7, 1.9 and 38.6 mg·l -1 , respectively.We conclude that there is considerable concentration of clarithromycin and its 14-OH metabolite in alveolar cells, and to a lesser extent in bronchial tissue and ELF; this implies efficacy against susceptible organisms at these sites.

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Section: Discussioncontrasting

confidence: 86%

The levels of clarithromycin and its 14-hydroxy metabolite in the lung

Honeybourne¹,

Kees²,

Andrews³

et al. 1994

Eur Respir J

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“…Craig This study also emphasizes an important shortcoming of the current methods of susceptibility testing: the inability to account for active metabolites. The role of an active metabolite in the efficacy of the parent compound has been discussed by other investigators (9,13,16,17,29). In certain situations (e.g., clarithromycin for Haemophilus influenzae), the presence of the active metabolite is required for adequate activity against specific organisms.…”

Section: Resultsmentioning

confidence: 99%

In vitro activities of metronidazole and its hydroxy metabolite against Bacteroides spp

Pendland

Piscitelli

Schreckenberger

et al. 1994

Antimicrob Agents Chemother

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Metronidazole is metabolized to two major oxidative products: an acid metabolite and a hydroxy metabolite.While the activity of the acid metabolite is negligible, the activity of the hydroxy metabolite is approximately 65% of the activity of the parent drug. Pharmacokinetic studies of metronidazole and its hydroxy metabolite have shown that the MICs of both compounds remain above the MICs for most anaerobic organisms over an 8-h dosing interval. By a checkerboard assay, the combined activities of metronidazole and the hydroxy metabolite were examined against 4 quality control strains of Bacteroides species. Macrobroth tube dilutions were set up with Wilkins-Chalgren broth. Serial twofold dilutions of each agent were performed to achieve final concentrations ranging from 0.06 to 4.0 ,ug/ml. The MICs for Bacteroides fragilis and B. distasonis were 1.0 ,ug/ml for both parent drug and metabolite. For B. thetaiotaomicron and B. ovatus, the MICs of metronidazole and the hydroxy metabolite were 1.0 and 2.0 ,g/ml, respectively. Synergy was determined by calculating the fractional inhibitory concentration (FIC) index. The interpretative criteria for the FIC index were as follows: synergy, FIC '0.5; partial synergy, 0.51 to 0.75; indifference, FIC 0.76 to 4.0; and antagonism, FIC >4.0. Partial synergy was observed for the four anaerobes tested, with FIC indices ranging from 0.63 to 0.75. On the basis of this data, in vitro susceptibilities to agents such as metronidazole may ultimately require reevaluation to account for active metabolites.The activity of metronidazole against anaerobes has been recognized for over 30 years (27). This drug is highly active against anaerobic gram-negative bacilli, including members of the Bacteroides fragilis group (24,26). Excellent bactericidal activity, few adverse effects, and reasonable cost are the primary reasons why this agent is considered one of the drugs of choice in the treatment of anaerobic infections.Metronidazole is metabolized to two major oxidative products: 1-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole (the hydroxy metabolite) and 1-acetic acid-2-methyl-5-nitroimidazole (the acid metabolite) (28) (Fig. 1). After administration of a single dose (500 mg) of metronidazole, peak concentrations in serum are approximately 10 ptg/ml. The concentration of the hydroxy metabolite is roughly one-third, or about 3 ,ug/ml, with a corresponding half-life in serum of 9 to 10 h, which is slightly longer than that for the parent compound (18).While the activity of the acid metabolite against anaerobes is negligible, the activity of the hydroxy metabolite is approximately 65% of the activity of the parent drug (15). In studies with clinical isolates, the MICs for 90% of organisms tested were 2 ,ug/ml for both metronidazole and its hydroxy metabolite, with the MICs of both agents consistently reported within 1 or 2 dilutions of each other (15,23). Pharmacokinetic studies have shown that the concentrations of both compounds in serum remain above the MICs for most anaerobic organisms o...

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“…WIN-57273 was less effective than clarithromycin (P < 0.05) on day 7. When the efficacies of the regimens against strain LV-2 were compared two by two, clarithromycin plus minocycline plus 14-OH clarithromycin was more effective than clarithromycin alone on day 4 (11). In conclusion, this metabolite with a longer half-life than clarithromycin allows prolonged efficacy, with an amount of active drug (clarithromycin plus 14-OH clarithromycin) in the serum close to twice the concentration of clarithromycin.…”

Section: Resultsmentioning

confidence: 99%

“…In patients with AIDS treated with clarithromycin (2 g/day), the peak level of clarithromycin in serum was accompanied by a very similar concentration of 14-hydroxy-clarithromycin (1, * Corresponding author. 4). This human metabolite has a longer half-life than clarithromycin, and its trough level is higher than that of clarithromycin.…”

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confidence: 99%

Activities of WIN-57273, minocycline, clarithromycin, and 14-hydroxy-clarithromycin against Mycobacterium avium complex in human macrophages

Cohen

Perronne

Truffot-Pernot

et al. 1992

Antimicrob Agents Chemother

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The activities of the fluoroquinolone WIN-57273, 14-OH clarithromycin (a human metabolite of clarithromycin), and minocycline against two virulent strains of Mycobacteium avium complex were evaluated in a model of intracellular infection and compared with that of clarithromycin. Human monocyte-derived macrophages were infected at day 6 of culture. Intracellular CFU at 60 min and intracellular and supernatant CFU on days 4 and 7 were counted after inoculation. The concentrations used, which were equal to peak levels in serum, were 3 pLg of WIN-57273 per ml (MICs for the two strains, 1 a.g/ml), 4 mg of 14-OH clarithromycin per ml (MICs, 8 and 2 Fg/ml, respectively, at pH 7.4), 4 ,g of minocycline per ml (MICs, 64 and 32 Fg/ml, respectively), and 4 ag of clarithromycin per ml (MICs, 2 and 0.5 ILg/ml, respectively, at pH 7.4). On day 7, compared with controls, WIN-57273, minocycline (P < 0.02), clarithromycin, or different combinations of clarithromycin and the other drugs (P < 0.001) slowed the intracellular replication of strain MO-1. 14-OH clarithromycin (P < 0.02), clarithromycin (P < 0.02), 14-OH darithromycin plus darithromycin (P < 0.01), clarithromycin plus minocycline, or clarithromycin plus minocycline plus 14-OH darithromycin (P < 0.001) slowed the intracellular replication of strain LV-2. WIN-57273 was less effective than carithromycin against strain MO-1 (P < 0.05). Clarithromycin plus 14-OH clarithromycin plus minocycline (P < 0.02) was more effective than clarithromycin alone against strain LV-2. Thus, clarithromycin plus minocycline, which corresponds in humans to three active molecules, may exhibit a better efficacy than clarithromycin in this model.Mycobacterium avium complex, a primarily intracellular bacterium which multiplies within phagocytic cells, frequently causes infection in patients with AIDS (7,20 (14). Minocycline is a longer-acting tetracycline derivative whose in vitro activity against M. avium complex was reported by Tsukamura in 1980 (18). Recently, in view of the high activity of a clarithromycin and minocycline combination against Mycobacterium leprae (13), it seemed interesting to test the activity of this combination against M. avium complex. In patients with AIDS treated with clarithromycin (2 g/day), the peak level of clarithromycin in serum was accompanied by a very similar concentration of 14-hydroxy-clarithromycin (1, * Corresponding author. 4). This human metabolite has a longer half-life than clarithromycin, and its trough level is higher than that of clarithromycin. Thus, 14-OH clarithromycin could participate in the therapeutic efficacy of clarithromycin in humans. The efficacy of this metabolite, which is not present in mice, cannot be assessed by clarithromycin treatment of infected mice.The aim of the present study was to evaluate, in a cell model, the activities of WIN-57273, minocycline, 14-OH clarithromycin alone, and 14-OH clarithromycin in combination with other drugs against M. avium complex multiplication within human macrophages. These activities were compar...

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The activity of clarithromycin and its 14-hydroxy metabolite against Haemophilus influenzae, determined by in-vitro and serum bactericidal tests

Cited by 43 publications

References 0 publications

The levels of clarithromycin and its 14-hydroxy metabolite in the lung

The levels of clarithromycin and its 14-hydroxy metabolite in the lung

In vitro activities of metronidazole and its hydroxy metabolite against Bacteroides spp

Activities of WIN-57273, minocycline, clarithromycin, and 14-hydroxy-clarithromycin against Mycobacterium avium complex in human macrophages

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