The increasing emergence of penicillin-resistant (P') strains of Streptococcus pneumoniae could pose a therapeutic problem in the next few years. Ceftriaxone (CRO), a broad-spectrum cephalosporin, exhibits a smaller increase in MICs against pr S. pneumoniae strains than amoxicillin (AMO) (usually referred as to the "gold standard" therapy for pneumococcal infections). Therefore, we compared their respective efficacies in a leukopenic Swiss mouse model of pneumococcal pneumonia. Infection was induced with two serotype 19 strains: a penicillin-susceptible (PS) strain (MICs of <0.01 for penicillin, 0.03 for AMO, and 0.03 for CRO) and a pr strain (MICs of 4 for penicillin, 2 for AMO, and 0.5 for CRO). Untreated mice died within 2 or 3 days. Against the PS strain, the minimal protective dose (two subcutaneous injections at 12-h intervals for 3 days) for both CRO and AMO was 5 mg/kg of body weight (87% survivors). Ten-fold-increased doses of CRO (50 mg/kg) gave similar protection (75% survivors) against the pr strain, whereas 20-and 40-fold-increased doses of AMO protected 0 and 34% of the animals, respectively, against the PS strain. CRO had a marked and prolonged antibacterial effect in the lungs (2.7-log-unit reduction of CFU in 24 h after a single 50-mg/kg injection) against the Pr strain in comparison with AMO. A standard dosage of 50 mg of CRO per kg in mice resulted in peak levels in serum and protein binding comparable to those observed with 1 g given intravenously in humans. This dosage remained effective against a highly pr S. pneumoniae strain in this model. The microbiological activity and pharmacodynamic and pharmacokinetic properties of CRO (time during which concentrations exceed the MIC for the test pathogen [AtMIC], .8 h; and peak/MIC ratio, >90 for free active drug) accounted for its efficacy relative to AMO (50 mg/kg: AtMIC, <2 h; peak/MIC ratio, <25) against the highly Pr S. pneumoniae strain used in this study.

The increasing emergence of penicillin-resistant and multiresistant strains of Streptococcus pneumoniae may pose a problem in coming years. We therefore compared sparfloxacin, a new fluoroquinolone with improved potency against streptococci, with amoxicillin, the "gold standard" in this setting, and another fluoroquinolone, ciprofloxacin, in a mouse pneumonia model. Their efficacies against penicillin-susceptible (serotype 3), macrolide-resistant (serotype 1), penicillin-resistant (serotype 23), and multiresistant (serotype 6) S. pneumoniae strains were evaluated. Immunocompetent Swiss mice (serotypes 1 and 3) and leukopenic mice (serotypes 6 and 23) were infected by peroral tracheal delivery of 10' to 10' CFU. Subcutaneous injections of antibiotics were initiated at 6, 18, 48, or 72 h after infection (six injections at 12-h intervals). In the immunocompetent mice, 100%o survival was obtained with sparfloxacin (50 mg/kg) and amoxicillin (5 mg/kg) against both penicillin-susceptible and macrolide-resistant strains; ciprofloxacin gave signifcantly lower survival rates. Two to four injections of sparfloxacin completely cleared bacteria from lungs and blood; the most rapid eradication was achieved with amoxicillin. Sparfloxacin also fully protected leukopenic mice against penicillin-resistant strains. The dose of amoxicillin (50 mgkg) required to protect mice and eradicate penicillin-resistant and multiresistant strains was 10 times higher than that effective against penicillin-susceptible strains. The microbiological and pharmacokinetic properties of sparfloxacin (e.g., the time during which concentrations exceed the MIC of the test pathogen) accounted for its efficacy against susceptible and resistant strains of S. pneumoniae in this model. Sparfloxacin (AT-4140) is a new quinolone with a broad spectrum of activity against both gram-positive and gramnegative bacteria (10, 11). Its potency against gram-negative organisms is similar to that of ciprofloxacin and greater than that of ofloxacin, enoxacin, or norfloxacin. Against grampositive organisms, sparfloxacin is more potent than the other quinolones (15). Given orally (p.o.) sparfloxacin is highly effective against systemic infections due to Staphylococcus aureus, Streptococcus pyogenes, Escherichia coli, and Pseudomonas aeruginosa in mice and is more potent than the other quinolones (15). The pharmacokinetics of sparfloxacin result in good absorption following oral administration, good tissue penetration, and a long half-life in plasma and tissues (14).Streptococcus pneumoniae remains the leading cause of community-acquired pneumonia (12). In addition, there is an increasing emergence of respiratory tract pathogens resistant to the most widely used drugs, i.e., penicillin G and macrolides (3, 9). We therefore compared the efficacy of sparfloxacin with that of another fluoroquinolone, ciprofloxacin, in acute and subacute mouse models of S. pneumoniae pneumonia induced by penicillin-susceptible (P ), penicillinresistant (PR), macrolide-resistant (M ), and multire...

We determined the ocular kinetics of pefloxacin, a new fluoroquinolone, when administered by the intramuscular route to albino and pigmented rabbits. In serum of albino rabbits, the area under the concentration-time curve (AUC) for the experimental period was 31.4 ± 1.07 ,ug. h/ml (mean ± standard deviation); the AUCs in the aqueous and vitreous humors were high (10.5 ± 1.90 and 12.4 ± 3.79 ,ug h/ml, respectively). Pefloxacin was found in the avascular ocular tissues (30.15 ± 3.79 ,ug-h/ml in the cornea and 6.98 ± 1.06 ,ug * h/ml in the lens). In the vascularized tissues, the penetration ratio, defined as tissue AUC/serum AUC, was more than 1. The good intraocular diffusion of pefloxacin might be related to its low molecular weight and to its strong lipophilicity and could explain its clinical efficacy in the treatment of endophthalmitis. In pigmented rabbits, pefloxacin levels were high in the iris (1525 ± 328 ,g. h/ml, versus 40.2 ± 5.08 ,Ag. h/ml in albino rabbits) and chorioretina (2600 ± 422 ,ug h/ml, versus 48.3 ± 7.52 ,ug. h/ml in albino rabbits), suggesting that it binds to the pigmentary apparatus. Eye infections are rare but generally serious, often leading to the loss of vision since numerous ocular tissues consist of thin membranes which are rapidly destroyed by microorganisms.When administered systemically, most antibiotics show poor ocular penetration, especially in the vitreous humor, since they must cross the blood-ocular barriers to reach the aqueous humor and retina before diffusing passively into the vitreous humor (8).Pefloxacin [1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-methyl-1-piperazinyl)-quinoline-3 carboxylic acid] is a new fluoroquinolone. It has been shown to have exceptionally good diffusion in tissues (10). After systemic administration, it has been found in the aqueous humor and lenses of patients undergoing cataract extraction (6, 9, 13).The purpose of this study was to assess the kinetics of pefloxacin in the different structures of the rabbit eye when administered by the intramuscular route. Albino and pigmented rabbits were used to determine the role of the pigmentary apparatus.MATERIALS AND METHODS Pharmacokinetic studies. Twenty-eight rabbits, each weighing approximately 2.5 kg, were used.Fourteen albino rabbits (New Zealand White) and 14 pigmented rabbits (Fauve de Bourgogne) were given a single intramuscular injection of 50 mg of pefloxacin (Roger-Bellon Laboratories, Paris, France) per kg of body weight.Blood samples were obtained prior to sacrifice by femoral artery puncture. The animals were killed with sodium pentobarbital 1, 2, 3, 5, 7, 9, or 11 h after antibiotic administration.Aqueous and vitreous samples were aspirated by puncture with a 23-gauge needle mounted on a tuberculin syringe. The eyes were removed and cleaned of conjunctival tissue and blood to avoid contamination by blood. They were immedi-* Corresponding author.ately stored at -80°C in order to minimize diffusion of the antibiotic (1).Assay. Pefloxacin (mesylate dihydrate), norfloxacin (4803 P), and intern...