In-vitro studies with ciprofloxacin, a new 4-quinolone compound

Pefloxacin and ciprofloxacin are two new quinoline carboxylic acid derivatives that have activity in vitro against a wide range of gram-negative bacteria, including Pseudomonas aeruginosa. Using a well-standardized model of Pseudomonas pneumonia in neutropenic guinea pigs, we tested the efficacy in vivo of these new agents. Both were highly effective in increasing survival and decreasing bacterial counts in the lungs of surviving animals. Pefloxacin and ciprofloxacin were significantly better (P < 0.05) than aminoglycosides or beta-lactams tested in prior studies with this model, and they were as effective as combination therapy with aminoglycosides and beta-lactams. Resistance to either ciprofloxacin or pefloxacin did not emerge during the study period. Further studies with these drugs in the therapy of Pseudomonas sp. infections are warranted.Pefloxacin and ciprofloxacin are two new quinoline carboxylic acid derivatives (12,15). Although structurally similar to nalidixic acid, the spectrum of activity of pefloxacin and ciprofloxacin includes Enterobacteriaceae, Pseudomonas sp., and many gram-positive cocci. Both drugs are well absorbed orally, have serum half-lives of 8.6 and 3.9 h, respectively, and reach concentrations in serum well above the MIC for many bacterial species (3, 6). Extensive in vitro studies have shown that ciprofloxacin has a MIC90 of -1 g/ml, whereas pefloxacin has a MIC90 of .2 ,ug/ml for many of the above-mentioned bacteria (2,5,14). It is of special interest that both of these antimicrobial agents are highly active against Pseudomonas aeruginosa, including multiply drug-resistant strains (2, 11).The purpose of this study was to examine the effectiveness of pefloxacin and ciprofloxacin against induced P. aeruginosa pneumonia in neutropenic guinea pigs. MATERIALS AND METHODSCiprofloxacin was obtained from Miles Pharmaceuticals, West Haven, Conn. Pefloxacin mesylate was obtained from Rhone-Poulenc, Paris, France.The MIC of each agent for the P5 strain of P. aeruginosa was determined in Mueller-Hinton broth supplemented with Mg2+ and Ca2+ by the macro-tube dilution method, using a standard inoculum of 5 log10 CFU/ml (13). The MBC was defined as the lowest concentration of drug that killed 99.9% of the original inoculum.Time-kill studies were performed with each antimicrobial agent, using concentrations which approximated the serum concentrations at peak levels. Logarithmic-phase organisms were added to supplemented Mueller-Hinton broth containing 12 ,ug of pefloxacin per ml, 4 ,ug of ciprofloxacin per ml, or no antibiotic and were incubated at 35°C. Samples were removed and quantitatively cultured before and after 4, 8, and 24 h of incubation.To determine the serum half-life (t412) of each drug and develop the therapeutic regimens, preliminary drug dosing studies were performed in groups of five normal guinea pigs. Blood was obtained by cardiac puncture 0.5, 1, 2, 3, 4, 6, and 8 h after an intramuscular injection of pefloxacin (25 mg/kg) or ciprofloxacin (either 10 or 20 mg/kg). Concentratio...

Section: Discussionmentioning

confidence: 94%

“…Reeves et al demonstrated rapid killing in vitro of both logarithmic-and stationary-phase organisms by ciprofloxacin (8). Clinical studies have demonstrated the importance of a rapid bactericidal effect in the treatment of gram-negative bacillary infections in the neutropenic host (16).…”

Section: Discussionmentioning

confidence: 99%

Activities of pefloxacin and ciprofloxacin in experimentally induced Pseudomonas pneumonia in neutropenic guinea pigs

Gordin¹,

Hackbarth²,

Scott³

et al. 1985

“…The activity of E-3846 increased at acid pH; in contrast, acid pH caused a pronounced decrease in the activity of norfioxacin and ciprofloxacin. In vivo, E-3846 demonstrated excellent therapeutic efficacy in treating experimental S. faecalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa cystitis and pyelonephritis in rats.The newer DNA gyrase subunit A inhibitors, such as amifloxacin (6, 14, 22), ciprofloxacin (1,8,23, 31), difloxacin (9, 26), enoxacin (4, 18, 20), irloxacin (5, 17), norfloxacin (3, 12, 13, 15), ofloxacin (10, 24), and perfloxacin (11, 27) are distinguished from earlier compounds such as nalidixic acid or oxolinic acid by modifications at positions 6, 7, and 8 on the ring structure. The addition of a fluorine atom to position 6 and modifications at position 7 resulted in an enormous increase in the antibacterial activity of these compounds (25).…”

mentioning

confidence: 99%

“…The newer DNA gyrase subunit A inhibitors, such as amifloxacin (6, 14, 22), ciprofloxacin (1,8,23, 31), difloxacin (9, 26), enoxacin (4, 18, 20), irloxacin (5, 17), norfloxacin (3, 12, 13, 15), ofloxacin (10, 24), and perfloxacin (11, 27) are distinguished from earlier compounds such as nalidixic acid or oxolinic acid by modifications at positions 6, 7, and 8 on the ring structure. The addition of a fluorine atom to position 6 and modifications at position 7 resulted in an enormous increase in the antibacterial activity of these compounds (25).…”

mentioning

confidence: 99%

Activity of E-3846, a new fluoroquinolone, in vitro and in experimental cystitis and pyelonephritis in rats

Gargallo

Moros

Coll

et al. 1988

The in vitro antibacterial activity of E-3846, a new fluoroquinolone carboxylic acid derivative with a pyrrol ring substituent at position 7, was evaluated in comparison with norfloxacin and ciprofloxacin. E-3846 was more active than the reference quinolones against Staphylococcus species, including methicillin-resistant strains. E-3846 was similar to ciprofloxacin and more active than norfloxacin against Streptococcus (Enterococcus) faecalis. In general, E-3846 was more active than norfloxacin against members of the family Enterobacteriaceae, but less active than ciprofloxacin. For Pseudomonas aeruginosa, the MICs giving 90% inhibition for E-3846, norfloxacin, and ciprofloxacin were 2, 1, and 0.25 ,ug/ml, respectively. The activity of E-3846 increased at acid pH; in contrast, acid pH caused a pronounced decrease in the activity of norfioxacin and ciprofloxacin. In vivo, E-3846 demonstrated excellent therapeutic efficacy in treating experimental S. faecalis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Pseudomonas aeruginosa cystitis and pyelonephritis in rats.The newer DNA gyrase subunit A inhibitors, such as amifloxacin (6, 14, 22), ciprofloxacin (1,8,23, 31), difloxacin (9, 26), enoxacin (4, 18, 20), irloxacin (5, 17), norfloxacin (3, 12, 13, 15), ofloxacin (10, 24), and perfloxacin (11, 27) are distinguished from earlier compounds such as nalidixic acid or oxolinic acid by modifications at positions 6, 7, and 8 on the ring structure. The addition of a fluorine atom to position 6 and modifications at position 7 resulted in an enormous increase in the antibacterial activity of these compounds (25).E-3846 (6-fluoro-1-cyclopropyl-1,4-dihydro-4-oxo-7[pyrrol-1-yl]-quinolone-3-carboxylic acid [ Fig. 1]) is a new fluoroquinolone antibacterial agent with a pyrrol ring at position 7 of the molecule. Other compounds with a 7-pyrrol ring substituent are irloxacin (17) and E-3604 (29).In this report, we describe E-3846 and compare its in vitro antibacterial activity with those of norfloxacin and ciprofloxacin against a wide variety of organisms. We also examined the in vivo efficacy of E-3846 in the treatment of experimental urinary tract infections in rats.

“…The frequency of endocarditis caused by strains of S. aureus resistant to methicillin (MRSA) is increasing (16). Vancomycin alone or in combination with rifampin or gentamicin is recommended for the therapy of patients with MRSA endocarditis (3,16,21).Ciprofloxacin, a carboxyquinolone, was reportedly bactericidal in vitro against strains of MSSA and MRSA and was fourfold more active in vitro against S. aureus than was norfloxacin or enoxacin (6,10,11,14, 17,18). Accordingly, ciprofloxacin might be useful therapy for patients with staphylococcal endocarditis.…”

mentioning

confidence: 99%

Ciprofloxacin therapy of experimental endocarditis caused by methicillin-susceptible or methicillin-resistant Staphylococcus aureus

Fernández-Guerrero

Rouse

Henry

et al. 1988

Ciprofloxacin was more effective (P < 0.01) than either imipenem or nafcillin therapy of experimental methicillin-susceptible Staphylococcus aureus endocarditis in rabbits after 2 or 3 days of treatment. There was no significant difference between results of treatment of methicillin-susceptible S. aureus experimental endocarditis with ciprofloxacin and results with the combination of nafcillin and gentamicin. Ciprofloxacin was more effective (P < 0.01) than vancomycin therapy of experimental methicillin-resistant S. aureus endocarditis after 3 days of treatment. After 5 days of treatment, there was no significant difference between the results of treatment of experimental methicillin-resistant S. aureus endocarditis with ciprofloxacin and results with vancomycin.Staphylococcus aureus is the second most common cause of infective endocarditis, accounting for 25 to 35% of cases, and is associated with frequent complications, including metastatic abscesses and rapid cardiac valve destruction resulting in heart failure (2, 5). Current antimicrobial therapy for patients with methicillin-susceptible Staphylococcus aureus (MSSA) endocarditis consists of administration of a beta-lactam with or without gentamicin or the use of vancomycin (1, 15). Imipenem was effective therapy for MSSA experimental endocarditis and for infective endocarditis in humans (8,20). The frequency of endocarditis caused by strains of S. aureus resistant to methicillin (MRSA) is increasing (16). Vancomycin alone or in combination with rifampin or gentamicin is recommended for the therapy of patients with MRSA endocarditis (3,16,21).Ciprofloxacin, a carboxyquinolone, was reportedly bactericidal in vitro against strains of MSSA and MRSA and was fourfold more active in vitro against S. aureus than was norfloxacin or enoxacin (6,10,11,14, 17,18). Accordingly, ciprofloxacin might be useful therapy for patients with staphylococcal endocarditis. The purpose of this study was to determine the efficacy of ciprofloxacin therapy of MSSA or MRSA experimental endocarditis and to compare the results of therapy with those resulting from treatment of animals with nafcillin, vancomycin, or imipenem, alone or combined with gentamicin. MATERIALS AND METHODSIn vitro studies. Four strains of S. aureus isolated from patients with infective endocarditis were used; two were MSSA and two were MRSA. The microorganisms were stored in defibrinated sheep blood at -70°C. Before testing, each strain was thawed and subcultured in tryptic soy agar containing 5% sheep blood.A macrodilution method was used for susceptibility testing (21). Inocula were prepared from broth cultures in the log phase of growth to yield an inoculum size of .5.5 x 105 CFU of staphylococci per ml and were inoculated into serial * Corresponding author.twofold dilutions of antimicrobial agent in Mueller-Hinton broth. Subcultures were made for confirmation of purity and quantitation of the inoculum size. Tubes containing the inoculum in serially diluted concentrations of antimicrobial agents were incubated f...