ceftriaxone and Disease-Models--Animal

A series of novel 7β-[2-(2-aminothiazole-4-yl)-2-(Z)-(alkoxyimino)acetamido]-cephalosporins having pyridinium-linked acyl cyanamide at the C-3 position were prepared and their antibacterial activities and pharmacokinetics profiles were evaluated. Most of the compounds exhibited potent antibacterial activities against penicillin-resistant Streptococcus pneumoniae (PRSP) and β-lactamase non-producing penicillin-resistant Haemophilus influenzae (BLNAR). Introduction of a propenyl group between the cephalospoin core and the side chains at the C-3 position improved the pharmacokinetics profile. Among these compounds, 7β-[2-(2-aminothiazole-4-yl)-2-(Z)- (alkoxyimino)acetamido]-3-(pyridin-1-ium-1-yl)prop-1-en-1-yl)cephalosporins (32j) showed well-balanced antibacterial activity against S. pneumoniae and H. influenzae which included resistant strains and also other Gram-positive or Gram-negative pathogens. Furthermore, 32j showed a long half-life comparable to that of Ceftriaxone in mice and monkeys.

Topics: Animals; Anti-Infective Agents; Bacteria; Cephalosporins; Cyanamide; Disease Models, Animal; Half-Life; Haplorhini; Male; Mice; Microbial Sensitivity Tests; Molecular Structure; Structure-Activity Relationship

Daptomycin is a novel lipopeptide antibiotic with excellent activity against Gram-positive bacterial pathogens, but its therapeutic value for the treatment of invasive pneumococcal disease compared to that for the treatment of pneumococcal pneumonia is incompletely defined. We investigated the efficacy of daptomycin in two models of Streptococcus pneumoniae-induced lung infection, i.e., pneumococcal pneumonia and septic pneumococcal disease. Mice were infected with a bioluminescent, invasive serotype 2 S. pneumoniae strain or a less virulent serotype 19 S. pneumoniae strain and were then given semitherapeutic or therapeutic daptomycin or ceftriaxone. Readouts included survival; bacterial loads; and septic disease progression, as determined by biophotonic imaging. Semitherapeutic daptomycin treatment fully protected the mice against the progression of septic disease induced by serotype 2 S. pneumoniae, while therapeutic treatment of the mice with daptomycin or ceftriaxone led to approximately 70% or approximately 60% survival, respectively. In contrast, mice infected with serotype 19 S. pneumoniae developed severe pneumonia and lung leakage even in the presence of increased intra-alveolar daptomycin levels, resulting in only 40% survival, whereas the ceftriaxone-treated mice had 100% survival. Together, although daptomycin demonstrates little efficacy in the treatment of pneumococcal pneumonia, daptomycin is highly effective in preventing S. pneumoniae-induced septic death, thus possibly offering a therapeutic option for patients with life-threatening septic pneumococcal disease.

Topics: Animals; Anti-Bacterial Agents; Ceftriaxone; Daptomycin; Disease Models, Animal; Mice; Mice, Inbred C57BL; Pneumococcal Infections; Pneumonia, Pneumococcal; Sepsis; Streptococcus pneumoniae

Antibiotic-induced bacteriolysis exacerbates inflammation and brain damage in bacterial meningitis. Here the quality and temporal kinetics of cerebrospinal fluid (CSF) inflammation were assessed in an infant rat pneumococcal meningitis model for the nonbacteriolytic antibiotic daptomycin versus ceftriaxone. Daptomycin led to lower CSF concentrations of interleukin 1beta (IL-1beta), IL-10, IL-18, monocyte chemoattractant protein 1 (MCP-1), and macrophage inflammatory protein 1 alpha (MIP-1alpha) (P < 0.05). In experimental pneumococcal meningitis, daptomycin treatment resulted in more rapid bacterial killing, lower CSF inflammation, and less brain damage than ceftriaxone treatment.

Topics: Animals; Animals, Newborn; Anti-Bacterial Agents; Ceftriaxone; Cerebrospinal Fluid; Daptomycin; Disease Models, Animal; Humans; Inflammation; Meningitis, Pneumococcal; Rats; Rats, Wistar; Treatment Outcome

Although earlier pleuromutilin analogues showed potent in vitro antibacterial activity against some Gram-positive pathogens, their in vivo efficacy was low because of insufficient pharmacokinetic properties. We designed novel thioether pleuromutilin derivatives having a purine ring as a polar and water solubilizing group and identified a promising pleuromutilin analogue 6 with good solubility in water ( approximately 50 mg/mL). Compound 6 exhibited excellent in vitro and in vivo antibacterial activity against some Gram-positive strains, including drug-resistant pathogens.

Topics: Animals; Anti-Bacterial Agents; Disease Models, Animal; Diterpenes; Dose-Response Relationship, Drug; Drug Design; Drug Resistance, Bacterial; Gram-Negative Bacteria; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Mice; Microbial Sensitivity Tests; Molecular Structure; Pleuromutilins; Polycyclic Compounds; Solubility; Stereoisomerism; Water

Daptomycin monotherapy was superior to ceftriaxone monotherapy and was highly efficacious in experimental pneumococcal meningitis, sterilizing the cerebrospinal fluid (CSF) of three of three rabbits after 4 to 6 h. With daptomycin therapy only a negligible release of [(3)H]choline as marker of cell wall lysis was detectable in the CSF, peaking around 250 cpm/min after 4 h, compared to a peak of around 2,400 cpm/min after 4 to 6 h for the ceftriaxone-treated rabbits.

Topics: Animals; Anti-Bacterial Agents; Bacteriolysis; Ceftriaxone; Cell Wall; Cerebrospinal Fluid; Choline; Daptomycin; Disease Models, Animal; Humans; Meningitis, Pneumococcal; Microbial Sensitivity Tests; Penicillin Resistance; Rabbits; Streptococcus pneumoniae; Treatment Outcome; Tritium

Bacteriolytic antibiotics cause the release of bacterial components that augment the host inflammatory response, which in turn contributes to the pathophysiology of brain injury in bacterial meningitis. In the present study, antibiotic therapy with nonbacteriolytic daptomycin was compared with that of bacteriolytic ceftriaxone in experimental pneumococcal meningitis, and the treatments were evaluated for their effects on inflammation and brain injury. Eleven-day-old rats were injected intracisternally with 1.3 x 10(4) +/- 0.5 x 10(4) CFU of Streptococcus pneumoniae serotype 3 and randomized to therapy with ceftriaxone (100 mg/kg of body weight subcutaneously [s.c.]; n = 55) or daptomycin (50 mg/kg s.c.; n = 56) starting at 18 h after infection. The cerebrospinal fluid (CSF) was assessed for bacterial counts, matrix metalloproteinase-9 levels, and tumor necrosis factor alpha levels at different time intervals after infection. Cortical brain damage was evaluated at 40 h after infection. Daptomycin cleared the bacteria more efficiently from the CSF than ceftriaxone within 2 h after the initiation of therapy (log(10) 3.6 +/- 1.0 and log(10) 6.3 +/- 1.4 CFU/ml, respectively; P < 0.02); reduced the inflammatory host reaction, as assessed by the matrix metalloproteinase-9 concentration in CSF 40 h after infection (P < 0.005); and prevented the development of cortical injury (cortical injury present in 0/30 and 7/28 animals, respectively; P < 0.004). Compared to ceftriaxone, daptomycin cleared the bacteria from the CSF more rapidly and caused less CSF inflammation. This combined effect provides an explanation for the observation that daptomycin prevented the development of cortical brain injury in experimental pneumococcal meningitis. Further research is needed to investigate whether nonbacteriolytic antibiotic therapy with daptomycin represents an advantageous alternative over current bacteriolytic antibiotic therapies for the treatment of pneumococcal meningitis.

Topics: Animals; Anti-Bacterial Agents; Brain Injuries; Ceftriaxone; Cerebral Cortex; Cerebrospinal Fluid; Daptomycin; Disease Models, Animal; Humans; Inflammation; Meningitis, Pneumococcal; Random Allocation; Rats; Treatment Outcome

Several recent outbreaks of Clostridium difficile-associated disease (CDAD) have been attributed to the emergence of an epidemic strain with increased resistance to fluoroquinolone antibiotics. Some clinical studies have suggested that fluoroquinolones with enhanced antianaerobic activity (i.e., gatifloxacin and moxifloxacin) may have a greater propensity to induce CDAD than ciprofloxacin and levofloxacin do. We examined the effects of subcutaneous fluoroquinolone treatment on in vitro growth of and toxin production by epidemic and nonepidemic C. difficile isolates in cecal contents of mice and evaluated the potential for these agents to inhibit fluoroquinolone-susceptible isolates during treatment. When C. difficile isolates were inoculated into cecal contents collected 2 days after the final antibiotic dose, gatifloxacin and moxifloxacin promoted significantly more growth and toxin production than ciprofloxacin and levofloxacin did. During treatment, gatifloxacin and moxifloxacin inhibited growth of fluoroquinolone-susceptible but not fluoroquinolone-resistant isolates. Ciprofloxacin and levofloxacin promoted growth of C. difficile when administered at higher doses (i.e., 20 times the human dose in mg/kg of body weight), and levofloxacin inhibited growth of fluoroquinolone-susceptible, but not fluoroquinolone-resistant, C. difficile isolates when administered in combination with ceftriaxone. Thus, fluoroquinolones with enhanced antianaerobic activity (i.e., gatifloxacin and moxifloxacin) promoted C. difficile growth to a greater extent than did ciprofloxacin and levofloxacin in this model. However, our findings suggest that fluoroquinolones may exert selective pressure favoring the emergence of epidemic fluoroquinolone-resistant C. difficile strains by inhibiting fluoroquinolone-susceptible but not fluoroquinolone-resistant isolates during treatment and that agents such as levofloxacin or ciprofloxacin can exert such selective pressure when administered in combination with antibiotics that disrupt the anaerobic microflora.

Topics: Anaerobiosis; Animals; Anti-Infective Agents; Bacterial Toxins; Cecum; Clostridioides difficile; Disease Models, Animal; Disease Outbreaks; Drug Resistance, Bacterial; Enterocolitis, Pseudomembranous; Fluoroquinolones; Humans; Mice; Microbial Sensitivity Tests