Comparative efficacies of ciprofloxacin, amoxicillin, amoxicillin-clavulanic acid, and cefaclor against experimental Streptococcus pneumoniae respiratory infections in mice

A mouse protection model was used to investigate the association of the pharmacokinetics and pharmacodynamics with the in vivo efficacy of ciprofloxacin compared with that of penicillin G in the treatment of mice infected with Streptococcus pneumoniae ATCC 6303. Mice were inoculated intraperitoneally with 10 times the minimum lethal dose of S. pneumoniae. For determination of the 50% protective dose, subcutaneous antibiotics were begun 1 h after infection and were continued for 24 h. The 50% protective doses of ciprofloxacin and penicillin G were 25.52 + 1.95 and 0.307 ± 0.006 mg/kg of body weight, respectively, an 83-fold difference in efficacy. For 100%Y protection with penicillin G, the time that the drug concentration needed to remain above the MIC was 51 min, a value easily achieved in most clinical situations. For 100%7 protection with ciprofloxacin, the peak concentration/MIC ratio must reach a value of 10.6. This ratio is rarely achieved with this drug against S. pneumoniae in clinical practice. These pharmacodynamic differences probably contribute to the reported differences in clinical success between these agents.Ciprofloxacin, a fluoroquinolone antibiotic, has excellent activity against most aerobic gram-negative bacteria, with achievable levels in serum (1.5 to 2.9 ,ug/ml following a 500-mg oral dose and 2.7 to 4.2 ,ug/ml following a 750-mg oral dose) greatly exceeding the MICs for most important pathogens such as members of the family Enterobacteriaceae (3,17,18,26). Ciprofloxacin's activity against gram-positive bacteria, however, is somewhat weaker, especially against organisms such as Streptococcus pneumoniae, for which the MICs for 50% (0.5 to 2.0 ,ug/ml) and 90% (1.0 to 4.0 ,ug/ml) of strains tested are closer to achievable peak levels of the drug in serum (5,25).Clinical failures have occurred when ciprofloxacin has been used to treat pneumococcal infections in patients at our institution, and these have been described in several other published reports (7,14).The purpose of the present study was to evaluate the in vivo effectiveness and pharmacokinetics of ciprofloxacin in the protection of mice inoculated with a virulent strain of pneumococcus. Our aim was to determine the doses of ciprofloxacin and penicillin G required to protect 50% (PD50) and 100% (PD100) of mice after intraperitoneal injection of S. pneumoniae. MATERIALS AND METHODSAnimals, bacteria, and antibiotics. Swiss albino mice weighing approximately 23 g were obtained from Taconic Laboratories, Germantown, N.Y. S. pneumoniae ATCC 6303 serotype 3 was used throughout the study. Bacteria were passaged periodically on blood agar plates to maintain viability. Ciprofloxacin powder for intravenous use and penicillin G sodium for intravenous use were obtained from * Corresponding author. 234Miles Laboratories, West Haven, Conn., and Squibb Laboratories, Princeton, N.J., respectively.Bacterial and animal studies. MICs were determined in Mueller-Hinton broth (Difco Laboratories, Detroit, Mich.) by a microtiter dilution method (23). The m...

Section: Discussionsupporting

confidence: 91%

Evaluation of the efficacy of ciprofloxacin against Streptococcus pneumoniae by using a mouse protection model

Sullivan

Cooper

Nightingale

et al. 1993

“…Determination of whether drugs with higher intrapulmonary concentrations would have greater clinical efficacy will require prospective controlled trials. Failures of ciprofloxacin in the treatment of pneumococcal pneumonia in an animal model (16) and in humans (27) have been described. Baldwin et al (4) have concluded that subtherapeutic intrapulmonary concentrations might be responsible for treatment failures.…”

Section: Discussionmentioning

confidence: 99%

Single-dose intrapulmonary pharmacokinetics of azithromycin, clarithromycin, ciprofloxacin, and cefuroxime in volunteer subjects

Conte

Golden

Duncan

et al. 1996

136

The intrapulmonary pharmacokinetics of azithromycin, clarithromycin, ciprofloxacin, and cefuroxime were studied in 68 volunteers who received single, oral doses of azithromycin (0.5 g), clarithormycin (0.5 g), ciprofloxacin (0.5 g), or cefuroxime (0.5 g). In subgroups of four subjects each, the subjects underwent bronchoscopy and bronchoalveolar lavage at timed intervals following drug administration. Drug concentrations, including those of 14-hydroxyclarithromycin (14H), were determined in serum, bronchoalveolar lavage fluid, and alveolar cells (ACs) by high-pressure liquid chromatography. Concentrations in epithelial lining fluid (ELF) were calculated by the urea diffusion method. The maximum observed concentrations (mean +/- standard deviation) of azithromycin, clarithromycin, 14H, ciprofloxacin, and cefuroxime in serum were 0.13 +/- 0.07, 1.0 +/- 0.6, 0.60 +/- 0.41, 0.95 +/- 0.32, and 1.1 +/- 0.3 microgram/ml, respectively (all at 6 h). None of the antibiotics except clarithromycin (39.6 +/- 41.1 micrograms/ml) was detectable in ELF at the 6-h bronchoscopy. The movement into and persistence in cells was different for azithromycin and clarithromycin. In ACs azithromycin was not detectable at 6 h, reached its highest concentration at 120 h, and exhibited the greatest area under the curve (7,403 micrograms.hr ml-1). The peak concentration of clarithromycin (181 +/- 94.1 micrograms/ml) was greater and occurred earlier (6 h), but the area under the curve (2,006 micrograms.hr ml-1) was less than that observed for azithromycin. 14H was detectable in ACs at 6 h (40.3 +/- 5.2 micrograms/ml) and 12 h (32.8 +/- 57.2 micrograms/ml). The peak concentration of ciprofloxacin occurred at 6 h (4.3 +/- 5.2 micrograms/ml), and the area under the curve was 35.0 micrograms.hr ml-1. The data indicate that after the administration of a single dose, azithromycin, clarithromycin, and ciprofloxacin penetrated into ACs in therapeutic concentrations and that only clarithromycin was present in ELF. The correlation of these kinetic observations with clinical efficacy or toxicity was not investigated and is unclear, but the data provide a basis for further kinetic and clinical studies.

“…The doses of antibiotics administered to the mice were those used in previously reported experimental infections in mice (4,10,12,13,29,32). They were selected to achieve about the same peak levels (or, more exactly, early concentrations) in the sera of mice as are achieved in the sera of humans (see Table 2).…”

Section: Methodsmentioning

confidence: 99%

Assessment of a fluoroquinolone, three beta-lactams, two aminoglycosides, and a cycline in treatment of murine Yersinia pestis infection

Bonacorsi

Scavizzi

Guiyoule

et al. 1994

Amoxicillin, cefotaxime, ceftriaxone, gentamicin, doxycycline, and ofloxacin were active in vitro, like the reference drug streptomycin, against the virulent strain Yersinia pestis 6/69M. The comparative efficacies of these drugs in vivo were evaluated in a standardized and reproducible mouse model of systemic infection. Each antibiotic was injected intravenously once, at 24 h postinfection, and then repeatedly during 48 h. In vivo results were measured by counting the viable bacteria recovered from the whole spleens of mice sacrificed at selected times. All the drugs were manifestly successful; ceftriaxone, ofloxacine, and the reference drug were the most effective. Therefore, gentamicin and doxycycline could be used, depending on the clinical forms of the Y. pestis infection. Further investigations on beta-lactams, especially those used in the present study, could be carried out to confirm or not confirm their activities against Y. pestis. Ofloxacin appeared to be as active and to perform as rapidly as streptomycin in the treatment of murine Y. pestis infection, which is in agreement with the previous successes obtained with the use of fluoroquinolones in the treatment of murine infections caused by other pathogenic yersiniae.Three pathogenic species are included in the genus Yersinia. Y enterocolitica and Y pseudotuberculosis essentially cause gastroenteritis and occasionally septicemia. Y pestis, which was discovered in 1894 by Alexandre Yersin, is the agent of plague.Despite the efforts of public health workers to control plague, this infection still has a widespread distribution in the world (7,20,22,25,35). During the last decade (1980 to 1989), 21 countries notified the World Health Organization of almost 10,000 cases of plague, and the global fatality rate was 11.5%, with peaks in some countries exceeding 35% (35). If, at the moment, the worldwide incidence seems to be stable, a few countries regularly report an increasing number of cases. In the four past decades (the 1950s, 1960s, 1970s, and 1980s), the United States has recorded 10, 28, 105, and 179 cases of plague, respectively (6, 35). Septicemic plague, which is difficult to recognize, may represent 20 to 25% of the cases of plague in the United States (17, 34). Secondary localizations, for example, pulmonary or meningeal, may complicate 6% of cases of bubonic or septicemic plague (3, 5) and up to now have been characterized by a high death rate, in some reports rising to 33% (2, 17).Forty years ago, Meyer (23) considered streptomycin, chloramphenicol, and tetracyclines to be reference drugs for the treatment of plague, and they are still recommended for that use today (3). This limited antibiotic choice can be a serious handicap because of (i) localization of the disease (e.g., meningitis), (ii) underlying disease, or (iii) antibiotic side effects.In the face of this dilemma, it seemed to us that it would be useful to evaluate the in vivo comparative efficacies of newer antibiotics like fluoroquinolones and extended-spectrum cephalosporins agains...