The therapeutic response of cephalosporin-treated E. coli pyelonephritis of the rat, in relation to variations of the infection model.

In the E. coli pyelonephritis, induced in female Wistar rats by retrograde infection (high pressure reflux), we investigated the influence of 1) the time of commencement of therapy, 2) the renal bacterial counts, i.e. the inflammatory activity of the pyelonephritis after endovesical instillation of cultures with different bacterial concentrations, and 3) the level of infection resistance of the experimental animal strain on the therapeutic response of the model infection with single doses of cefoxitin (150 mg/ml) and cefotaxime (5 mg/ml). Early commencement of therapy post inoculation was therapeutically advantageous provided the intrarenal multiplication of the infective organisms was not delayed or the initial bacterial concentrations were not too high. The mild form of pyelonephritis with lower renal bacterial concentrations and poor inflammatory activity after endovesical instillation of a low inoculum (10(4) cfu/ml) was less amenable to treatment than the inflammatory active pyelonephritis with high renal bacterial counts, using a high inoculum (10(7) cfu/ml). High renal bacterial counts after retrograde inoculation of an E. coli culture of 10(8) cfu/ml resulted in significant reduction of bacterial counts 48, 72 and 96 h post infectionem, with i.m. application of cefoxitin 12 h prior. For Wistar rat strain Bor:WIST, which showed a stronger infection resistance with lower renal bacterial concentrations and a stronger tendency to spontaneous healing, application of a single dose of cefotaxime (5 mg/ml) was therapeutically ineffective, whereas, in contrast, with Han: WIST rats the acute phase of E. coli pyelonephritis could be treated effectively.

Standardization of a model of E. coli-pyelonephritis in rats.

The validity of preclinical testing of antibiotics in animal experiments is highly dependent on the quality and, especially, the standardizability of the infection model. Some of the factors associated with standardization of the acute phases of infection are demonstrated for experimental pyelonephritis in female albino Wistar rats after transuretheral infection. The renal bacterial count and infection rate are correlated to the volume and bacterial concentration of the instilled E. coli suspension. Strains of albino Wistar rats from different breeding institutions show differing resistance to the infection. E. coli pyelonephritis establishes more easily in female Wistar rats of strain Han: WIST than in strain Bor: WIST. Following dissection of the animals, the infected kidneys can be stored for at least 4 weeks at -30 degrees C or in liquid nitrogen, because the bacterial counts remain constant. However, in frozen renal homogenates the bacterial counts fall rapidly. During the first 4 post-infection days the bacterial content of the kidneys is relatively constant. The period 30-72 h post infection is especially suitable for therapeutic studies.

Ceftazidime, ceftizoxime, cefotaxime and HR 221 in experimental chronic Escherichia coli pyelonephritis in rats.

The therapeutic efficacy and pharmacokinetics of the cephalosporins ceftazidime, ceftizoxime, cefotaxime and HR 221 were studied in animal experiments. The animal model used was experimental estrogen-induced or non-induced chronic Escherichia coli pyelonephritis in rats. The animals were treated with 5 mg cephalosporin/kg twice daily for one week. Each of the cephalosporins tested led to a significant decrease in renal bacterial counts, in spite of the low doses given. Ceftazidime was significantly more active than HR 221 in both experimental models, although the serum levels of HR 221 were higher and were maintained for a longer period of time than those of ceftazidime. Differences in pharmacokinetic properties (influenced by metabolic stability and protein binding) could be the reason for the differences in therapeutic activity, since the in vitro antimicrobial activity of each of the cephalosporins tested was very similar against the test strain.