In-vitro activity of clinafloxacin, trovafloxacin, and ciprofloxacin

The in vitro activities of sitafloxacin, ciprofloxacin, trovafloxacin, levofloxacin, clinafloxacin, gatifloxacin, and moxifloxacin against 5,046 gram-negative bacteria, 3,344 gram-positive cocci, and 406 anaerobes were determined. Sitafloxacin was the most active agent against gram-positive cocci and anaerobes. Against Enterobacteriaceae and nonfermenters, its activity was either equivalent to or better than that of clinafloxacin.Sitafloxacin (DU-6859a) is a new fluoroquinolone active against gram-positive and gram-negative bacteria, including anaerobes (3,7,13). In the present study, the in vitro activities of sitafloxacin against a large number of contemporary and clinically relevant bacterial isolates were determined and compared with those of ciprofloxacin, clinafloxacin, gatifloxacin, levofloxacin, moxifloxacin, and trovafloxacin.A total of 8,796 bacterial strains were tested which had been isolated between April 1997 and February 1999 from patients in 24 university hospitals in 14 European countries, 1 in Israel, and 3 in South Africa. Only one isolate per patient was permitted. Strains were reidentified in our laboratory using a combination of standard methods and either the VITEK or the API system (BioMerieux, s'Hertogenbosch, The Netherlands). MICs were determined by a microdilution method described by the National Committee for Clinical Laboratory Standards (15), using cation-adjusted Mueller-Hinton broth. For testing Streptococcus spp. and Neisseria spp., 5% lysed horse blood was added. Haemophilus spp. were tested using Haemophilus test medium. The inoculum was adjusted to 5 ϫ 10 5 CFU/ml. Plates were read after 20 to 24 h of incubation at 35°C in ambient air. Anaerobic bacteria were tested with WilkinsChalgren broth and a final inoculum of 10 6 CFU/ml. Plates were read after 48 h of incubation at 35°C in an anaerobic environment (16).The results of susceptibility testing are presented as the MICs at which 50 and 90% of the isolates tested are inhibited (MIC 50 and MIC 90 ) and the ranges of MICs (Table 1). Sitafloxacin was very active against enterobacterial species, inhibiting 96.9% of the 3,129 strains at a concentration of 1 g/ml. The MIC 50 s ranged from Յ0.008 to 1 g/ml, and the MIC 90 s ranged from 0.015 to 2 g/ml. The MIC 90 for Providencia spp. was the highest (2 g/ml), followed by those for Enterobacter aerogenes and Escherichia coli (1 g/ml for each). These three species also exhibited the highest rates of ciprofloxacin resistance (51.6, 38.5, and 14.6%, respectively). The MIC 90 s of sitafloxacin for Citrobacter koseri, Klebsiella oxytoca, Pantoea agglomerans, Proteus vulgaris, salmonellae, Serratia liquefaciens, Shigella spp., and Yersinia enterocolitica ranged from 0.015 to 0.12 g/ml and were similar to those of ciprofloxacin. However, sitafloxacin was four times more active than ciprofloxacin against Citrobacter freundii, Klebsiella pneumoniae, Morganella morganii, and Serratia marcescens and at least eight times more active against E. aerogenes, Enterobacter cloacae, E. coli, and Prot...

supporting

confidence: 84%

In Vitro Activities of Sitafloxacin (DU-6859a) and Six Other Fluoroquinolones against 8,796 Clinical Bacterial Isolates

Milatovic

Schmitz

Brisse

et al. 2000

“…and the Enterobacteriaceae; the MICs of clinafloxacin at which 90% of isolates are inhibited (MIC 90 s) are similar to or lower than those of ciprofloxacin (17,34). Clinafloxacin is also highly active against most species of anaerobes, and its MIC 90 s are substantially lower than those of ciprofloxacin (6,36).…”

mentioning

confidence: 99%

Clinafloxacin versus Piperacillin-Tazobactam in Treatment of Patients with Severe Skin and Soft Tissue Infections

Siami

Christou

Eiseman³

et al. 2001

Patients (n ‫؍‬ 409) with severe skin and soft tissue infections (SSTIs) were randomized to receive clinafloxacin or piperacillin-tazobactam (plus optional vancomycin for methicillin-resistant cocci), administered intravenously, with the option to switch to oral medication. Most patients had cellulitis, wound infections, or diabetic foot infections. Staphylococcus aureus, Enterococcus faecalis, and Pseudomonas aeruginosa were the most common baseline pathogens. Fewer baseline pathogens were resistant to clinafloxacin (1.8%) than to piperacillin-tazobactam (6.2%) (P ‫؍‬ 0.001). The clinafloxacin and piperacillin-tazobactam groups did not differ significantly in clinical cure rates (68.8 and 65.2%, respectively) or microbiologic eradication rates (61.5 and 57.2%). Clinafloxacin yielded higher eradication rates for all three of the most common pathogenic species, although no differences were statistically significant. Within the power of this study, the overall frequency of adverse events was similar (P ‫؍‬ 0.577) in the two treatment groups. Drug-associated adverse events (P ‫؍‬ 0.050) and treatment discontinuations (P ‫؍‬ 0.052) were marginally more frequent in the clinafloxacin group, primarily due to phototoxicity in outpatients receiving clinafloxacin. Although most cases of phototoxicity were mild to moderate, four cases were reported as severe. In summary, clinafloxacin monotherapy was equivalent in effectiveness to therapy with piperacillin-tazobactam plus optional vancomycin in the treatment of hospitalized patients with severe SSTIs.Skin and soft tissue infections (SSTIs), such as spontaneous lymphangitis or cellulitis, and especially complicated infections, such as wound and surgical infections or diabetic foot ulcers, often require hospitalization and intravenous (i.v.) antibacterial treatment. These infections are caused by a mixture of aerobic and anaerobic organisms and are responsible for increased morbidity, prolonged hospital stay, and increased health care costs (3,13,19).Staphylococcus aureus and streptococci; gram-negative bacteria such as Pseudomonas aeruginosa, Enterobacteriaceae, and Enterococcus spp.; and anaerobes such as Bacteroides fragilis are frequently isolated (8,12,13,18,32 Frequently used antimicrobial agents have included expandedspectrum cephalosporins (e.g., cefoxitin, cefotetan, cefmetazole), imipenem-cilastatin, ␤-lactam-␤-lactamase inhibitor combinations (e.g., piperacillin-tazobactam, ticarcillin-clavulanate), and fluoroquinolones (13,14,15,18,20,35). However, emerging resistance, particularly among S. aureus, P. aeruginosa, and enterococci, is making the choice of treatment increasingly more difficult (23).Clinafloxacin is an extended-spectrum fluoroquinolone antibacterial that is bactericidal against S. aureus, including methicillin-resistant strains, and most strains of ciprofloxacinresistant S. aureus (7,33). Like other fluoroquinolones, clinafloxacin has activity against Pseudomonas spp. and the Enterobacteriaceae; the MICs of clinafloxacin at which 90% of isolates are ...

“…An observed late pharmacodynamic effect was most likely due to gut flora changes. Phenytoin has no effect on clinafloxacin pharmacokinetics, while phenytoin clearance is 15% lower during clinafloxacin administration.Clinafloxacin is a potent quinolone antibacterial with a broad range of activity that is of potential clinical importance in the management of serious infections, including those caused by many bacteria resistant to a wide variety of other antibiotics (5,6,7,11,16,27). It has been studied primarily in adults hospitalized for the treatment of serious and potentially life-threatening infections, including nosocomial pneumonia, community-acquired pneumonia, febrile neutropenia, complicated intra-abdominal infections, complicated skin and soft tissue infections, endocarditis, and acute gynecologic infections.…”

mentioning

confidence: 99%

Drug Interactions with Clinafloxacin

Randinitis¹,

Alvey²,

Koup³

et al. 2001

Many fluoroquinolone antibiotics are inhibitors of cytochrome P450 enzyme systems and may produce potentially important drug interactions when administered with other drugs. Studies were conducted to determine the effect of clinafloxacin on the pharmacokinetics of theophylline, caffeine, warfarin, and phenytoin, as well as the effect of phenytoin on the pharmacokinetics of clinafloxacin. Concomitant administration of 200 or 400 mg of clinafloxacin reduces mean theophylline clearance by approximately 50 and 70%, respectively, and reduces mean caffeine clearance by 84%. (R)-Warfarin concentrations in plasma during clinafloxacin administration are 32% higher and (S)-warfarin concentrations do not change during clinafloxacin treatment. An observed late pharmacodynamic effect was most likely due to gut flora changes. Phenytoin has no effect on clinafloxacin pharmacokinetics, while phenytoin clearance is 15% lower during clinafloxacin administration.Clinafloxacin is a potent quinolone antibacterial with a broad range of activity that is of potential clinical importance in the management of serious infections, including those caused by many bacteria resistant to a wide variety of other antibiotics (5,6,7,11,16,27). It has been studied primarily in adults hospitalized for the treatment of serious and potentially life-threatening infections, including nosocomial pneumonia, community-acquired pneumonia, febrile neutropenia, complicated intra-abdominal infections, complicated skin and soft tissue infections, endocarditis, and acute gynecologic infections.Clinafloxacin pharmacokinetics in healthy subjects have been reported previously (31). Following administration of 200-and 400-mg twice-daily intravenous doses, the mean values for total body clearance and volume of distribution are approximately 320 ml/min and 156 liters, respectively, and the mean terminal elimination half-life (t 1/2 ) is approximately 5.8 h. Clinafloxacin is approximately 50% bound to plasma protein, independent of concentration. Approximately 50 to 70% of a clinafloxacin dose is excreted unchanged in urine, indicating that renal clearance is the primary route of elimination. Clinafloxacin clearance is correlated to degree of renal function as measured by creatinine clearance (CL CR ). Based on the relationship between clinafloxacin clearance and CL CR , patients with CL CR values of Ͻ40 ml/min should have their daily clinafloxacin dose halved (34).The ability of clinafloxacin to inhibit seven major cytochrome P450 enzymes, CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4, was investigated using isoform-selective marker substrates and human liver microsomal preparations (T. F. Woolf and W. F. Trager, personal communication). Clinafloxacin was most effective in inhibiting CYP1A2 with nearly 50% inhibition observed at the 5 M concentration. CYP2A6, CYP2E1, and CYP3A4 were not inhibited even at a clinafloxacin concentration of 125 M. CYP2C19 was 15 and 75% inhibited at 5 and 125 M clinafloxacin concentrations, respectively. A weaker interaction...