Fosfomycin is a broad-spectrum agent with activity against Gram-positive and Gram-negative bacteria, including drug-resistant strains, such as extended-spectrumbeta-lactamase (ESBL)-producing and carbapenem-resistant (CR) Gram-negative rods. In the present study, the pharmacokinetic/pharmacodynamic (PK/PD) activity of ZTI-01 (fosfomycin for injection) was evaluated in the neutropenic murine thigh infection model against 5 Escherichia coli, 3 Klebsiella pneumoniae, and 2 Pseudomonas aeruginosa strains, including a subset with ESBL and CR phenotypes. The pharmacokinetics of ZTI-01 were examined in mice after subcutaneous administration of 3.125, 12.5, 50, 200, 400, and 800 mg/kg of body weight. The half-life ranged from 0.51 to 1.1 h, area under the concentration-time curve (AUC 0 -∞ ) ranged from 1.4 to 87 mg · h/liter, and maximum concentrations ranged from 0.6 to 42.4 mg/liter. Dose fractionation demonstrated the AUC/MIC ratio to be the PK/PD index most closely linked to efficacy (R 2 ϭ 0.70). Net stasis and bactericidal activity were observed against all strains. Net stasis was observed at 24-h AUC/MIC ratio values of 24, 21, and 15 for E. coli, K., pneumoniae and P. aeruginosa, respectively. For the Enterobacteriaceae group, stasis was noted at mean 24-h AUC/MIC ratio targets of 23 and 1-log kill at 83. Survival in mice infected with E. coli 145 was maximal at 24-h AUC/MIC ratio exposures of 9 to 43, which is comparable to the stasis exposures identified in the PK/PD studies. These results should prove useful for the design of clinical dosing regimens for ZTI-01 in the treatment of serious infections due to Enterobacteriaceae and Pseudomonas.

The debate over the influence of heterozygosity and homozygosity on developmental stability is ongoing, and rarely is an animal model found that represents these two genetic states in naturally occurring populations. Rivulus marmoratus (Pisces: Aplocheilidae), a small cyprinodontid fish indigenous to mangrove marshes of the western tropical Atlantic coast, may be an appropriate model. This species is well known as the only self-fertilizing hermaphroditic vertebrate, and populations normally consist of genetically diverse groups of homozygous clones. However, male fish are known from a few populations, and outcrossing has been documented from one area (Belize in Central America) where heterozygosity is the norm. Are there differences in developmental stability, as represented by fluctuating asymmetry (FA) and physical variability, between naturally occurring homozygous and heterozygous populations? Thirty-one meristic and morphometric characters in 180 fish from 10 populations were examined to determine physical variability. In addition, FA and the presence of physical anomalies were analyzed. Belize fish (heterozygous) were compared with eight other (homozygous) populations. To control for possible environmental effects, offspring of two populations (Belize and Florida) were reared at 25°C and similarly analyzed. The FA analyses and variability comparisons revealed no differences between heterozygous and homozygous populations, and the same was true for fish reared at a constant temperature. However, some populations (e.g., Brazil) were more variable than others. These results indicate that coadapted gene complexes may be more important than heterozygosity in canalizing developmental stability in this animal.Résumé : La controverse au sujet de l'influence de l'hétérozygotie et de l'homozygotie sur la stabilité du développe-ment se poursuit et il est difficile de trouver un modèle animal qui puisse représenter les deux conditions génétiques chez des populations naturelles. Rivulus marmoratus (Pisces : Aplocheilidae), un petit poisson cyprinodonte indigène des mangroves de l'Atlantique tropical occidental, est potentiellement un bon modèle. C'est la seule espèce de vertébré hermaphrodite à s'auto-féconder et les populations sont ordinairement constituées de groupes génétiquement diversifiés de clones homozygotes. Cependant, les mâles existent chez quelques populations et des croisements allogames ont pu être réalisés en une région (Bélize, l'Amerique centrale) où l'hétérozygotie est la condition normale. Existe-t-il des différences dans la stabilité du développement, telles que mesurées par l'asymétrie fluctuante et la variabilité physique, entre les populations naturelles homozygotes et hétérozygotes? Trente et une mesures méristiques et morphométriques relevées sur 180 poissons de 10 populations ont permis d'évaluer la variabilité physique. En outre, l'asymétrie fluctuante et la présence d'anomalies physiques ont été analysées. Les poissons du Bélize (hétérozygotes) ont été comparés à ceux de huit autres populati...

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