Meropenem Pharmacokinetics in the Newborn VAN DEN ANKER, John N; POKOMA, Pavla; KINZIG-SCHIPPERS, Martina ...
Antimicrobial Agents and Chemotherapy,
09/2009, Letnik:
53, Številka:
9
Journal Article
is considered a likely agent to be used as a bioweapon, and the use of a strain resistant to the first-line antimicrobial treatments is a concern. We determined treatment efficacies against a ...ciprofloxacin-resistant strain of
(Cip
Ames) in a murine inhalational anthrax model. Ten groups of 46 BALB/c mice were exposed by inhalation to 7 to 35 times the 50% lethal dose (LD
) of
Cip
Ames spores. Commencing at 36 h postexposure, groups were administered intraperitoneal doses of sterile water for injections (SWI) and ciprofloxacin alone (control groups), or ciprofloxacin combined with two antimicrobials, including meropenem-linezolid, meropenem-clindamycin, meropenem-rifampin, meropenem-doxycycline, penicillin-linezolid, penicillin-doxycycline, rifampin-linezolid, and rifampin-clindamycin, at appropriate dosing intervals (6 or 12 h) for the respective antibiotics. Ten mice per group were treated for 14 days and observed until day 28. The remaining animals were euthanized every 6 to 12 h, and blood, lungs, and spleens were collected for lethal factor (LF) and/or bacterial load determinations. All combination groups showed significant survival over the SWI and ciprofloxacin controls: meropenem-linezolid (
= 0.004), meropenem-clindamycin (
= 0.005), meropenem-rifampin (
= 0.012), meropenem-doxycycline (
= 0.032), penicillin-doxycycline (
= 0.012), penicillin-linezolid (
= 0.026), rifampin-linezolid (
= 0.001), and rifampin-clindamycin (
= 0.032). In controls, blood, lung, and spleen bacterial counts increased to terminal endpoints. In combination treatment groups, blood and spleen bacterial counts showed low/no colonies after 24-h treatments. The LF fell below the detection limits for all combination groups yet remained elevated in control groups. Combinations with linezolid had the greatest inhibitory effect on mean LF levels.
We have shown previously in animal model and in vitro systems that antimicrobial therapy intensity has a profound influence on subpopulations of resistant organisms. Little attention has been paid to ...the effect of therapy duration on resistant subpopulations. We examined the influence of therapy intensity (area under the concentration/time curve for 24 h:minimum inhibitory concentration AUC24:MIC ratio) and therapy duration on resistance emergence using an in vitro model of Staphylococcus aureus infection. AUC24:MIC ratios of ⩾100 were necessary to kill a substantial portion of the total population. Importantly, we demonstrated that therapy duration is a critical parameter. As the duration increased beyond 5 days, the intensity needed to suppress the antibiotic-resistant subpopulations increased, even when the initial bacterial kill was >4 log10 (cfu/mL). These findings were prospectively validated in an independent experiment in which exposures were calculated from the results of fitting a large mathematical model to all data simultaneously. All of the prospectively determined predictions were fulfilled in this validation experiment.
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