title: In vitro activity of clarithromycin alone and in combination with ciprofloxacin or levofloxacin against Legionella spp.: enhanced effect by the addition of the metabolite 14-hydroxy clarithromycin.
abstract: Clarithromycin is metabolized to an active metabolite, 14-hydroxy clarithromycin. These compounds have demonstrated excellent in vitro activity against Legionella species, with both agents having significantly lower MICs than erythromycin. Using a checkerboard assay, the activity of clarithromycin and its hydroxy metabolite, alone and in combination, was examined against 41 Legionella organisms. The activity of clarithromycin and 14-hydroxy clarithromycin, in a 2:1 ratio, plus ciprofloxacin or levofloxacin was also determined. Activity of the antibiotic combinations was determined by calculating the fractional inhibitory concentration index. An agar dilution method using buffered charcoal yeast extract media was used for susceptibility and synergy testing. An inoculum of 10(4) CFU/spot was used, with all plates incubated at 35 degrees C for 48 h. The MIC90 for clarithromycin or 14-hydroxy clarithromycin alone was 0.5, versus 0.25 microgram/mL for the combination. Additive effects were observed with clarithromycin and its hydroxy metabolite for 61% of the Legionella species, with fractional inhibitory concentration indices ranging from 0.63 to 1.25. The 14-hydroxy metabolite significantly increased the activity of both fluoroquinolone/clarithromycin combinations. Based on these data, in vitro susceptibility testing of agents such as clarithromycin should be reevaluated to account for the activity of active metabolites.
authors.affiliation: Department of Pharmacy Practice, University of Illinois, Chicago 60612, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Martin
authors.forename: S L
authors.initials: SL
authors.lastname: Pendland
authors.forename: C
authors.initials: C
authors.lastname: Chen
authors.forename: P C
authors.initials: PC
authors.lastname: Schreckenberger
authors.forename: L H
authors.initials: LH
authors.lastname: Danziger
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000378:metabolism; D000890:Anti-Infective Agents / Q000008:administration & dosage; D002939:Ciprofloxacin / Q000008:administration & dosage*; D017291:Clarithromycin / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000378:metabolism; D004352:Drug Resistance, Microbial; D004357:Drug Synergism; D004359:Drug Therapy, Combination / Q000008:administration & dosage*; D006801:Humans; D066298:In Vitro Techniques; D007875:Legionella / Q000187:drug effects* / Q000302:isolation & purification; D016952:Legionella pneumophila / Q000187:drug effects / Q000302:isolation & purification; D064704:Levofloxacin; D008826:Microbial Sensitivity Tests; D015242:Ofloxacin / Q000008:administration & dosage*
chemical_list: D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; C056228:14-hydroxyclarithromycin; D002939:Ciprofloxacin; D064704:Levofloxacin; D015242:Ofloxacin; D017291:Clarithromycin