title: In-vitro investigation of the antibacterial activity of agents which may be used for the oral treatment of lung infections in CF patients.
abstract: The effect of triple therapy with ciprofloxacin, trimethoprim and either sulphadiazine or sulphamethoxazole on the MICs and development of resistance of three strains of Pseudomonas aeruginosa, two strains of Staphylococcus aureus and one of Burkholderia cepacia was compared with that of single or dual therapy with these agents using an agar dilution method. Ciprofloxacin MICs were 0.2-0.8 mg/L for the P. aeruginosa and S. aureus strains. For trimethoprim the MIC ranges were 64-128 and 0.25-1 mg/L for P. aeruginosa and S. aureus, respectively. For the sulphonamides the ranges were 64-2500 and 20-39 mg/L for P. aeruginosa and S. aureus, respectively. All combinations of agents were effective at lower concentrations than the single agents. The combination of ciprofloxacin, sulphonamide and trimethoprim showed enhanced activity against all test organisms. The highest ciprofloxacin concentration was one-tenth of the normally attainable serum concentration of 2.5 mg/L. Thus peak plasma concentrations of > or =8 x MIC for ciprofloxacin against P. aeruginosa and S. aureus are theoretically achievable in the presence of clinically acceptable concentrations of trimethoprim and a sulphonamide, making the development of resistance less likely. The development of resistance, as shown by the proportional increase in MICs, was repressed by the triple regimen as compared with the development of resistance to agents used singly or in pairs. Killing curve determinations also demonstrated the advantage of the triple-agent therapy against all organisms tested: the combination of ciprofloxacin 0.5 mg/L, trimethoprim 1 mg/L and sulphadiazine 20 mg/L had an initial bactericidal effect against log-phase inocula of 10(6) cfu/mL of two clinical strains of P. aeruginosa and one clinical strain of S. aureus. The pseudomonas strains were reduced by 2-4 log cycles. Both recovered over 24 h but did not exceed the initial inoculum. The S. aureus was reduced to 10(2) cfu/mL in 4 h and did not recover over 24 h. A repeat dose of the triple therapy against the more resistant of the P. aeruginosa strains after 12 h also had a bactericidal effect. These data suggest the possibility of an effective exclusively oral therapy for the treatment of lung infections in cystic fibrosis patients.
authors.affiliation: School of Pharmacy, The Robert Gordon University, Schoolhill, Aberdeen, UK. r.richards@rgu.ac.uk
authors.forename: R M
authors.initials: RM
authors.lastname: Richards
authors.forename: V E
authors.initials: VE
authors.lastname: Hamilton
authors.forename: M R
authors.initials: MR
authors.lastname: Thomas
mesh_terms: D000284:Administration, Oral; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002939:Ciprofloxacin / Q000494:pharmacology / Q000627:therapeutic use; D003550:Cystic Fibrosis / Q000150:complications* / Q000382:microbiology; D004359:Drug Therapy, Combination; D006801:Humans; D008171:Lung Diseases / Q000188:drug therapy / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D011552:Pseudomonas Infections / Q000150:complications / Q000188:drug therapy; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D013203:Staphylococcal Infections / Q000150:complications / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D014295:Trimethoprim / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; D013449:Sulfonamides; D002939:Ciprofloxacin; D014295:Trimethoprim