Correlation of in-vitro activity and pharmacokinetic parameters with in-vivo effect of amoxycillin, co-amoxiclav and cefotaxime in a murine model of pneumococcal pneumonia

Abstract

In an attempt to determine the susceptibility breakpoints for amoxycillin, co-amoxiclav and cefotaxime in pneumococcal pneumonia, a neutropenic mouse model was established and tested with two strains having different susceptibility to penicillins and cefotaxime. With a penicillin-sensitive strain (MIC/MBC = 0.01/0.01 mg/L) the minimum dosage tested achieving significant cure was 2 mg/kg for amoxycillin, co-amoxiclav and cefotaxime. For the penicillin-insensitive strain (MIC/MBC = 1/2 mg/L), the minimum dosage tested giving significant cure was 50 mg/kg for amoxycillin and co-amoxiclav but 100 mg/kg for cefotaxime. Our results support the belief that MICs of amoxycillin, co-amoxiclav and cefotaxime for pneumococcal strains of < or = 0.5 or < or = 1 mg/L can be considered as clinically relevant susceptibility breakpoints.

Animal Models ofStreptococcus pneumoniaeDisease

“…They have widely been used for analyzing pathogenicity mechanisms of pneumonia (50,58,114,120,125,131), sepsis (109,131,251), and meningitis (59,95,160,268). In addition, outbred mice have also been employed to evaluate active and passive protection against pneumonia and sepsis (4, 115, 163) and the efficacy of antibiotic therapy against invasive pneumococcal disease (13,141,169,220,223). The host genetic factors controlling the response to infection by S. pneumoniae are still unknown.…”

“…Typically, strains of capsular serotypes 2, 3, 4, 5, and 6 are virulent in mice, whereas strains of types 14, 19, and 23 are relatively avirulent (21,39). The low virulence of many pneumococcal strains in rodents can be balanced by either using larger challenge doses (40) or neutropenic hosts (19,49,169,221,223).…”

“…Several groups have preferred serotype 3 and 6 strains isolated from patients with pneumococcal meningitis and have successfully induced this disease in the mouse, the rat, and the rabbit (26,35,69,76,85,95,145,192,268,269). Clinical isolates of serotypes 3, 6, 9, and 19 have also been employed in laboratory animal models to elucidate features of pneumococcal pneumonia and sepsis (12,14,40,49,196,223,234,251). For experimental otitis media, strains of serotypes 3, 4, 6, 7, 9, 11, 14, 19, and 23, which are the ones most commonly isolated from children with acute otitis, have been used (18,80,81,89,101,154).…”

Broad-Spectrum β-Lactam Antibiotics for Treating Experimental Peritonitis in Mice Due to Klebsiella pneumoniae Producing the Carbapenemase OXA-48

“…The 50% effective dose (ED 50 ; the single dose giving protection to 50% of the mice) was determined from two trials by the Probit method (5). In the first trial, drugs were given in 10-fold dilutions of 0.1 to 100 mg/kg to six mice in each treatment group (7,14,15).…”

Comparative efficacy of novobiocin and amoxicillin in experimental sepsis caused by β-lactam-susceptible and highly resistant pneumococci

“…The doses selected for amoxicillin administration were based on the results from a previous study by our group [26] which showed that the maximum amoxicillin concentrations attained in mouse serum after single doses of amoxicillin of 200 mg/kg and 50 mg/kg were 300 mg/L and 75 mg/L, respectively. However, such high amoxicillin concentrations cannot be achieved in patients following oral administration of usual dosages.…”