No abstract

The antibacterial activity of levofloxacin was compared with those of ofloxacin, ciprofloxacin, and other antibiotics. In general, levofloxacin was equally active or up to fourfold more active than ofloxacin against all 801 organisms tested. Levofloxacin was 64-fold more active than ciprofloxacin against Streptococcus pneumoniae and 2-to 4-fold more active than ciprofloxacin against Staphylococcus aureus, Xanthomonas maltophUia, and Bacteroides fragili&. Levofloxacin was two-to eightfold more active than ciprofloxacin against coagulasenegative staphylococci and Acinetobacter spp., although these improvements in potency may not be clinically relevant. Levofloxacin inhibited 90%o of streptococci when it was used at concentrations of 1 to 2 ;ag/ml. The therapeutic effects of levofloxacin were determined against acute systemic and localized infections in mice. For systemic infections, female mice (CF-1; weight, 20 2 g) * Corresponding author.were challenged with one 100% lethal dose (LD10o) by intraperitoneal injection of bacteria. Treatment was administered orally 1 and 3 h after infection. The 50% effective dose (ED50) was calculated on day 7 after infection. In another study, mice were challenged with 10Ox the LD50, and treatment was one dose given intravenously 1 h after infection.The efficacies of levofloxacin in pyelonephritis and pneumococcal lower respiratory tract infections (LRTIs) in mice were also determined and compared with those of ciprofloxacin. Pyelonephritis was established with Staphylococcus aureus by a previously described method (2). Treatment was oral, starting 1 and 4 h after infection, and was continued twice daily for a total of 4 days. Twenty-four hours after the last treatment, kidneys were excised, weighed, and homogenized, and viable bacterial counts were quantitated. LRTIs were established after nasal instillation of 2 x 107 CFU of Streptococcus pneumoniae into anesthetized mice. Oral treatment consisted of two doses given 24 h after infection. Twenty-four hours after treatment, the lungs were excised, weighed, and homogenized, and viable counts were quantitated. Concentrations of levofloxacin and ciprofloxacin in serum and tissue were assayed by an agar well diffusion method with E. coli OC 160 as the indicator organism.

FK037, a new parenteral cephalosporin, is an oxime-type cephem antibiotic with a 1-hydroxyethyl-5-aminopyrazole moiety at the 3 position. FK037 was evaluated for antimicrobial activity in vitro and in vivo. In vitro, FK037 was twofold or more active than ceftazidime, cefoperazone, cefotaxime, and ceftriaxone against Pseudomonas aeruginosa (MIC for 90%o of the strains [MIC.] = 32 ,ug/ml), members of the family Enterobacteriaceae (MIC90 5 2 ,ug/ml), group A streptococci (MIC9 0.015 ,g/ml), and methicillin-sensitive or -resistant coagulase-negative staphylococci (MIC90 = 2 and 16 ,ug/ml, respectively). In addition, the activity of FK037 was equal to or greater than that of ceftazidime, cefotaxime, or ceftriaxone against Streptococcus pneumoniae (MIC90 = 0.12 .g/ml) and methicillin-sensitive or -resistant Staphylococcus aureus (MIC90 = 2 and 16 ug/ml, respectively). FK037 was more active in vitro than cefepime (two-to fourfold) and cefpirome (twofold) against S. aureus. In murine systemic infection models, FK037 showed potent activity against P. aeruginosa, Escherichia coli, and methicillin-sensitive and methicillin-resistant S. aureus. FK037 was also efficacious in a mouse model of pyelonephritis caused by S. aureus or KlebsieUla pneumoniae and in a mouse model of pneumococcal pneumonia caused by S. pneumoniae. Additional studies on this compound to assess its potential clinical utility are warranted.Cephalosporins are very important in the treatment of bacterial infections because they exhibit broad antibacterial activities, have little toxicity, and are generally well tolerated (1). Structural modifications of the cephem nucleus have produced a variety of antimicrobial agents with improved, broad spectra of activity and ,-lactamase stability (8, 14). FK037 (Fig. 1) is a new parenteral cephalosporin (10) with the chemical formula erboard agar dilution method was used to evaluate the interaction of combined drugs. Synergy was determined by using the fractional inhibitory concentration index (9).Bactericidal activity. The MBCs of FK037 and ceftazidime were determined by a broth microdilution method (12). Compounds were serially diluted in Mueller-Hinton broth (MHB) cation supplemented as described by NCCLS. After incubation, negative broths were subcultured onto blood agar to determine the MBC. The lowest concentration of FK037 that exhibited 99.9% reduction of the numbers of colonies compared with the CFU in the initial inoculum was considered the MBC.Time-kill study. FK037 at two-and fourfold the MICs against Staphylococcus aureus OC2069 and Pseudomonas aeruginosa OC43 was tested in a time-kill study. Test organisms were grown overnight, diluted to 1 x 106 to 3 x 106 CFU/ml. One milliliter of this was added to MHB with and without FK037, resulting in a final inoculum of 3.5 x 105 CFU/ml. At 2, 4, 6, 8, and 24 h of incubation, 1-ml aliquots were removed, and viable cell counts were determined with Mueller-Hinton agar (MHA).Development of resistance. Two strains each of methicillinresistant and -sensitive S. aureus ...

Twelve strains of Streptococcus pneumoniae were serially exposed to increasing concentrations of levofloxacin, temafloxacin, ciprofloxacin and norfloxacin for five passages. Wild-type and passaged strains were tested for susceptibility to quinolones, macrolide and penicillin G. The MIC90 data showed a 2-fold increase for levofloxacin but a 32-fold increase for ciprofloxacin, a 16-fold increase for temafloxacin and an 8-fold increase for norfloxacin. Among 16 ciprofloxacin-induced resistant strains, 14 were susceptible to levofloxacin. No cross-resistance to other antibiotics was observed.

The in vitro activity of levofloxacin against coagulase-negative staphylococci (CNS) was investigated. In vitro, on the basis of MIC₉₀ values, levofloxacin was as active as ciprofloxacin, inhibiting both methicillin-sensitive and -resistant staphylococci at 0.5 μg/ml. The frequency of one-step development of levoflox-acin-resistant CNS was < 1 x 10^––9. After repeated transfer of CNS in the presence of increasing concentrations of levofloxacin or other quinolones, there were 4-fold increases in MIC₅₀ values for both levofloxacin and ofloxacin, whereas there were 64- to 128-fold increases for ciprofloxacin, norfloxacin and enoxacin. Based on MIC₅₀ values, the concentrations of 1 or 2 ug/ml are clinically relevant. The mutant strains induced by levofloxacin showed less virulence based on the LD₅₀ value in acute systemic murine infection.