Decrease in Bacterial Load Versus Resistance Selection of Pneumococcal Subpopulations by -Lactam Physiological Concentrations over Time: An In Vitro Pharmacodynamic Simulation

• Published in: Microbial drug resistance (Larchmont, N.Y.) Vol. 14; no. 1; p. 13
• Main Authors: Cafini, Fabio, Aguilar, Lorenzo, Sevillano, David, Gimnez, Maria-Jose, Alou, Luis, Fenoll, Asuncion, Echevarra, Olatz, Torrico, Martha, Gonzlez, Natalia, Coronel, Pilar, Prieto, Jose
• Format: Journal Article
• Language: English
• Published: New Rochelle Mary Ann Liebert, Inc 01.03.2008
• Subjects: Antibiotics; Bacteria; Drug resistance; Mutation; Streptococcus infections; Subpopulations
• ISSN: 1076-6294; 1931-8448
• DOI: 10.1089/mdr.2008.0783

To investigate -lactam effects on Streptococcus pneumoniae mixed cultures, a computerized pharmacodynamic model simulating over 24-hr concentrations obtained after several -lactam regimens was used. Strain 1 (no penicillin binding protein [PBP] mutations) and strain 2 (mutation in pbp1a) were penicillin/amoxicillin susceptible. Strain 3 (mutations in pbp1a, pbp2x, and pbp2b) and strain 4 (mutations in pbp1a, pbp2x, and pbp2b 10 changes) were penicillin/amoxicillin resistant. Initial inoculum was approximately 6 106 CFU (colony forming units)/ml (with a 1:1:1:1 proportion of each strain). Population analysis profile was performed pre- and postsimulations. Strain 1 exhibited the best fitness (growth over 24 hr) in individual cultures, and strain 2 did so in mixed cultures in antibiotic-free simulations. In antibiotic simulations with the mixed inocula, penicillin/amoxicillin-susceptible strains were eradicated with all study drugs (time that concentrations exceed the minimal inhibitory concentration [T > MIC 43]). Penicillin-resistant strains showed different evolution depending on the antibiotic: (a) cefditoren produced >2 log10 reduction of initial inocula at 1224 hr (T>MIC 45), with a remaining population growing in plates with 4 mg/L amoxicillin; (b) cefuroxime, cefixime, and cefaclor did not decrease initial inocula at 1224 hr (T > MIC 0), with minor subpopulations growing in plates with 4 mg/L amoxicillin; (c) amoxicillin produced 2.6 log10 decrease of initial inocula at 12 hr (T>MIC 47.5), but 1.1 log10 increase of initial inocula at 24 hr, with a significant population growing in plates with 4 mg/L amoxicillin. Antibiotic activity against mixed inocula (susceptible and resistant strains) depends on intrinsic activity (as well as its subsequent pharmacodynamic activity: T > MIC against resistant strains), and on possible selection of intra-strain-resistant subpopulations. [PUBLICATION ABSTRACT]