In vivo bactericidal activities of ciprofloxacin and pefloxacin in an experimental model of Serratia marcescens endocarditis

Abstract

The critical concentrations of pefloxacin and ciprofloxacin in serum, corresponding to the lowest concentration in serum able to achieve a 2-log-unit reduction in the CFU in vegetations after a 24-h exposure at a steady-state concentration obtained by a continuous intravenous infusion, were determined in an experimental model of Serratia marcescens endocarditis in rabbits. In vitro data showed that the MICs of ciprofloxacin and pefloxacin were 0.06 and 0.25 mg/liter, respectively. The killing curves indicated a maximum killing rate at a concentration four times that of the MICs. In vivo, the critical concentrations of pefloxacin and ciprofloxacin in serum were 0.4 and 0.24 mg/liter, respectively, corresponding to a concentration of four times the MICs.The fluoroquinolones are often used for the treatment of severe gram-negative infectious diseases. Although in vitro studies have suggested that their bactericidal activities are concentration dependent (2, 15), many in vivo factors (protein binding, serum half-life, local activity conditions such as pH, anaerobiosis, etc.) may also be involved (10). Moreover, early bactericidal activity in an antibiotic regimen is potentially important for the treatment of life-threatening infections. In a previous study (13), we defined the critical concentration of aminoglycosides in serum in an experimental model of Serratia marcescens endocarditis in rabbits. This in vivo parameter was defined by the lowest steady-state concentration in serum that was able to achieve a 2-log-unit reduction in CFU in endocarditis vegetations versus those in controls 24 h after the beginning of a continuous intravenous (i.v.) infusion. The critical concentration in serum (CCS), which defines the intrinsic activity of each antibiotic in vivo, is more relevant than the in vitro MIC for studying the in vivo concentration-activity relationship. The purpose of the present study was to investigate the CCSs of two fluoroquinolones in the same model of S. marcescens endocarditis.S. marcescens HN229 was used to induce experimental endocarditis. It was isolated from the urine of a hospitalized patient. This strain was resistant to rabbit serum. The two fluoroquinolones used were pefloxacin (Roger-Bellon, Paris, France) and ciprofloxacin (Bayer, Paris, France). The MIC of each antibiotic was determined by a Mueller-Hinton broth dilution technique (supplemented with Ca2' and Mg2+) (8), which was defined as the lowest concentration that produced no visible growth after 18 h of incubation in a 96-well microplate. The MBC corresponded to the lowest concentration that was able to achieve 0.1% surviving bacteria (8). A quinolone inhibitor (magnesium sulfate) was used to avoid a carryover phenomenon (6). By using the dynamic checkerboard method (4, 5), time-kill curves were drawn for each antibiotic at 11 concentrations (from 0.03 to 32 and from 0.015 to 16 mg/liter for pefloxacin and ciprofloxacin, respectively) in Mueller- surviving bacteria were counted after 0, 1.5, 3, 6, and 24 h of incubation by a semiautom...

Comparative efficacies of ciprofloxacin and pefloxacin alone or in combination with fosfomycin in experimental endocarditis induced by multidrug-susceptible and -resistant Pseudomonas aeruginosa

“…Antibiotic concentrations in serum for the ciprofloxacin and pefloxacin regimens were determined by a microbiological method using a clinical strain of Escherichia coli. For ciprofloxacin, measurable concentrations ranged from 0.03 to 1 mg/liter (coefficients of variation of 6 and 9% for 0.03 and 1 mg/liter, respectively; sensitivity limit, 0.03 mg/liter), and those for pefloxacin ranged from 0.5 to 4 mg/liter (coefficients of variation of 5 and 10% for 0.5 and 4 mg/liter, respectively; sensitivity limit, 0.25 mg/liter) (15). Concentrations of fosfomycin in serum were determined by capillary electrophoresis, a method recently validated in serum, over a concentration range of 2.5 to 200 g/ml.…”

“…A short treatment period (24 h) was chosen, since it corresponds to a critical endpoint for the prognosis of severely ill patients with septicemic P. aeruginosa infection and mimics the usual time of in vitro exposure. The pefloxacin dose of 64 mg/kg was initially chosen because a previous study (15) led us to expect a concentration in serum at least twice the in vitro MIC for the susceptible strain with this 24-h continuousinfusion dosage. Moreover, our in vitro data exhibited a clear synergy between pefloxacin and fosfomycin with a pefloxacin MIC in serum (1 mg/liter) that was one-half of the in vitro MIC.…”

“…Animals were sacrificed with an intravenous bolus of 100 mg of thiopental. At the time of sacrifice, aortic valve vegetations were excised, weighed, homogenized, and quantitatively cultured for 24 h at 37ЊC on Trypticase soy agar plates containing 10 mg of magnesium sulfate per liter to avoid a carryover effect, as previously described (15). Bacterial titers were expressed as log 10 CFU per gram of vegetation.…”

Serratia marcescens

“…Juvin et al [59] studied the MICs (and MBCs) of pefloxacin and ciprofloxacin for a S. marcescens strain and concluded that killing curves for the S. marcescens strain studied (but possibly not for others) were essentially time-dependent. Thus, the excellent intrinsic activity in vivo was probably caused mainly by the pharmacokinetics of the two drugs (long half-lives combined with rapid and homogeneous diffusion).…”

Assessment of Antibiogram of Biofield Energy Treated <i>Serratia marcescens</i>

“…Results reported the alteration of the sensitivity pattern of gentamicin from resistance to susceptible, with decreased MIC values by about two-fold in all the experimental treated groups after biofield treatment in S. marcescens as compared to the control. Similarly, tobramycin an aminoglycosides has been reported for its resistance pattern due to the presence of combination of aac(6')-Ia, aac(6')-Ic, and aac(6')-Ib genes [31]. Biofield energy treatment might act at enzymatic or genetic level, which may improve the susceptibility pattern and decreased the MIC of tobramycin against S. marcescens.…”