title: Activity of moxifloxacin against intracellular community-acquired methicillin-resistant Staphylococcus aureus: comparison with clindamycin, linezolid and co-trimoxazole and attempt at defining an intracellular susceptibility breakpoint.
abstract: BACKGROUND
  Co-trimoxazole, clindamycin and linezolid are used to treat community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) infections, but little is known about intracellular activity. Moxifloxacin is active against intracellular methicillin-susceptible S. aureus (MSSA), but CA-MRSA has not been studied.
  
  
  METHODS
  We used 12 clinical CA-MRSA, 1 MSSA overexpressing norA and 2 hospital-acquired MRSA (moxifloxacin MICs: 0.03 to 4 mg/L). Activity was assessed in broth and after phagocytosis by THP-1 macrophages or keratinocytes {concentration-dependent experiments [24 h of incubation] to determine relative potencies [EC(50)], static concentrations [C(s)] and maximal relative efficacies [E(max) (change in log(10) cfu compared with initial inoculum)] and time-dependent experiments [0-72 h] at human C(max)}.
  
  
  RESULTS
  Concentration-dependent experiments: in broth, EC(50) and C(s) were correlated with the MIC for all antibiotics, but moxifloxacin achieved significantly (P < 0.01) greater killing (more negative E(max)) than the comparators; and in THP-1 cells and keratinocytes, moxifloxacin acted more slowly but still reached a near bactericidal effect (2 to 3 log(10) cfu decrease) at 24 h with unchanged EC(50) and C(s) as long as its MIC was ≤0.125 mg/L (recursive partitioning analysis). Clindamycin and linezolid were static, and co-trimoxazole was unable to suppress the intracellular growth of CA-MRSA. At human C(max) in broth, moxifloxacin killed more rapidly and more extensively (≥5 log(10) cfu decrease at 10 h) than clindamycin (4 log(10) cfu at 48 h) or co-trimoxazole and linezolid (1-2 log(10) cfu at 72 h).
  
  
  CONCLUSIONS
  Moxifloxacin is active against both extracellular and intracellular CA-MRSA if the MIC is low, and is more effective than clindamycin, co-trimoxazole and linezolid.
authors.affiliation: Pharmacologie Cellulaire et Moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Lemaire
authors.forename: Klaudia
authors.initials: K
authors.lastname: Kosowska-Shick
authors.forename: Peter C
authors.initials: PC
authors.lastname: Appelbaum
authors.forename: Y
authors.initials: Y
authors.lastname: Glupczynski
authors.forename: Françoise
authors.initials: F
authors.lastname: Van Bambeke
authors.forename: Paul M
authors.initials: PM
authors.lastname: Tulkens
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001372:Aza Compounds / Q000494:pharmacology*; D002460:Cell Line; D002981:Clindamycin / Q000494:pharmacology; D017714:Community-Acquired Infections / Q000382:microbiology; D024841:Fluoroquinolones; D006801:Humans; D000069349:Linezolid; D008264:Macrophages / Q000382:microbiology; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000302:isolation & purification; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D000077266:Moxifloxacin; D023303:Oxazolidinones / Q000494:pharmacology; D010587:Phagocytosis; D011804:Quinolines / Q000494:pharmacology*; D013203:Staphylococcal Infections / Q000382:microbiology; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000494:pharmacology
chemical_list: D000081:Acetamides; D000900:Anti-Bacterial Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D023303:Oxazolidinones; D011804:Quinolines; D002981:Clindamycin; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D000069349:Linezolid; D000077266:Moxifloxacin