cefotaxime and Disease-Models--Animal

During the past decade there has been an increase in the percentage of resistant bacteria isolated from middle-ear effusions aspirated from infants and children who have had acute otitis media. At least nine oral antibiotics or combination agents are available for this indication. Cefixime, a third generation cephalosporin, has excellent in vitro activity against both beta-lactamase-negative and beta-lactamase-positive Haemophilus influenzae and Moraxella catarrhalis, good activity against Streptococcus pneumoniae and Streptococcus pyogenes but relatively poor activity against Staphylococcus aureus. In children cefixime is similar in effectiveness to amoxicillin and cefaclor, but diarrhea and stool changes are more common with cefixime. Amoxicillin is still preferred for initial empiric treatment of uncomplicated acute otitis media. Its major drawback is limited efficacy when beta-lactamase-producing bacteria are the causative organisms. Cefixime is a viable alternative to amoxicillin for infants and children with acute otitis media when: (1) a beta-lactamase-producing H. influenzae or M. catarrhalis is isolated from otorrhea or tympanocentesis; (2) the child has a history of delayed hypersensitivity to the penicillins but no history of hypersensitivity to the cephalosporins; (3) there is a high incidence of resistant bacteria in the community; (4) there is not clinical improvement with amoxicillin; or (5) once daily administration is more convenient.

Topics: Animals; Anti-Bacterial Agents; Cefixime; Cefotaxime; Child; Child, Preschool; Clinical Trials as Topic; Disease Models, Animal; Humans; In Vitro Techniques; Infant; Otitis Media

Klebsiella pneumoniae is an opportunistic pathogen associated with biofilm-based infections, which are intrinsically antibiotic resistant. Extracellular DNA plays a crucial role in biofilm formation and self-defence, with nucleases being proposed as promising agents for biofilm disruption. This study evaluated the in vitro and in vivo efficacy of DNase I in improving the activity of cefotaxime, amikacin, and ciprofloxacin against K. pneumoniae biofilms. K. pneumoniae ATCC 700603 and a clinical isolate from catheter-related bloodstream infection were cultured for biofilm formation on microtiter plates, and the antibiofilm activity of the antibiotics (0.03-64 mg/L), with or without bovine pancreatic DNase I (1-32 mg/L) was determined by XTT dye reduction test and viable counting. The effect of ciprofloxacin (2 mg/L) and DNase I (16 mg/L) was further evaluated in vitro on 1-cm-long silicon catheter segments, and in a mouse model of subcutaneous catheter-associated infection. Combination with DNase I did not improve the biofilm-preventive capacity of the three antibiotics or the biofilm-eradicating capacity of cefotaxime and amikacin. The biofilm-eradicating capacity of ciprofloxacin was increased by 8-fold and 4-fold in K. pneumoniae ATCC 700603 and clinical isolate, respectively, with DNase I. The combination therapy caused 99% reduction in biofilm biomass in the mouse model.

Topics: Amikacin; Animals; Anti-Bacterial Agents; Biofilms; Cattle; Cefotaxime; Ciprofloxacin; Deoxyribonuclease I; Disease Models, Animal; Klebsiella pneumoniae; Mice; Microbial Sensitivity Tests

Antibiotic resistance is a major challenge to global public health. Discovery of new antibiotics is slow and to ensure proper treatment of bacterial infections new strategies are needed. One way to curb the development of antibiotic resistance is to design drug combinations where the development of resistance against one drug leads to collateral sensitivity to the other drug. Here we study collateral sensitivity patterns of the globally distributed extended-spectrum β-lactamase CTX-M-15, and find three non-synonymous mutations with increased resistance against mecillinam or piperacillin-tazobactam that simultaneously confer full susceptibility to several cephalosporin drugs. We show in vitro and in mice that a combination of mecillinam and cefotaxime eliminates both wild-type and resistant CTX-M-15. Our results indicate that mecillinam and cefotaxime in combination constrain resistance evolution of CTX-M-15, and illustrate how drug combinations can be rationally designed to limit the resistance evolution of horizontally transferred genes by exploiting collateral sensitivity patterns.

Topics: Amdinocillin; Animals; Anti-Bacterial Agents; beta-Lactamases; beta-Lactams; Cefotaxime; Disease Models, Animal; Drug Combinations; Drug Resistance, Microbial; Escherichia coli; Female; Gene Transfer, Horizontal; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Mutation

The mortality rate associated with

Topics: Animals; Anti-Bacterial Agents; Cefotaxime; Ciprofloxacin; Colony Count, Microbial; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Female; Humans; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Minocycline; Sepsis; Survival Analysis; Tigecycline; Vibrio Infections; Vibrio vulnificus

To test the synergistic effect of Cpl-711 endolysin and antibiotics for antipneumococcal activity.. A combination of Cpl-711 and different antibiotics (amoxicillin, cefotaxime, levofloxacin and vancomycin) was tested in a checkerboard assay against several multidrug-resistant Streptococcus pneumoniae strains. Mouse and zebrafish models of pneumococcal sepsis were used to confirm the in vitro data.. The activity of Cpl-711 combined with amoxicillin or cefotaxime was synergistic in the bactericidal effect against a serotype 23F multiresistant clinical isolate of S. pneumoniae. Synergy between Cpl-711 and cefotaxime was validated using both mouse and zebrafish models.. Combination of Cpl-711 and cefotaxime may help in the treatment of diseases caused by multiresistant pneumococcal strains.

Topics: Animals; Anti-Bacterial Agents; Cefotaxime; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Drug Synergism; Female; Mice; Mice, Inbred BALB C; Muramidase; Pneumococcal Infections; Recombinant Fusion Proteins; Sepsis; Streptococcus Phages; Streptococcus pneumoniae; Zebrafish

Ser/Thr protein kinase (STK1) plays a critical role in cell wall biosynthesis of and drug resistance in methicillin-resistant Staphylococcus aureus (MRSA). MRSA strains lacking STK1 become susceptible to failing cephalosporins, such as Ceftriaxone and Cefotaxime. STK1, despite being nonessential protein for MRSA survival, it can serve as an important therapeutic agent for combination therapy. Here, we report a novel small molecule quinazoline compound, Inh2-B1, which specifically inhibits STK1 activity by directly binding to its ATP-binding catalytic domain. Functional analyses encompassing in vitro growth inhibition of MRSA, and in vivo protection studies in mice against the lethal MRSA challenge indicated that at high concentration neither Inh2-B1 nor Ceftriaxone or Cefotaxime alone was able to inhibit the growth of bacteria or protect the challenged mice. However, the growth of MRSA was inhibited, and a significant protection in mice against the bacterial challenge was observed at a micromolar concentration of Ceftriaxone or Cefotaxime in the presence of Inh2-B1. Cell-dependent minimal to no toxicity of Inh2-B1, and its abilities to down-regulate cell wall hydrolase genes and disrupt the biofilm formation of MRSA clearly indicated that Inh2-B1 serves as a therapeutically important "antibiotic-resistance-breaker," which enhances the bactericidal activity of Ceftriaxone/Cefotaxime against highly pathogenic MRSA infection.

Topics: Adenosine Triphosphate; Amino Acid Sequence; Animals; Anti-Bacterial Agents; Binding Sites; Biofilms; Catalytic Domain; Cefotaxime; Ceftriaxone; Cell Line; Cell Wall; Disease Models, Animal; Drug Resistance, Microbial; Drug Resistance, Multiple, Bacterial; Female; Gene Deletion; Genes, Bacterial; Humans; Methicillin-Resistant Staphylococcus aureus; Mice; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Sepsis; Small Molecule Libraries; Virulence Factors

We investigated the efficacies of cefotaxime (CTX) and amoxicillin (AMX)-clavulanate (CLA) (AMC) against extended-spectrum-β-lactamase (ESBL)-producing Escherichia coli in vitro and in a murine model of urinary tract infection (UTI). MICs, the checkerboard dilution method, and time-kill curves were used to explore the in vitro synergism between cefotaxime and amoxicillin-clavulanate against two isogenic E. coli strains-CFT073-RR and its transconjugant, CFT073-RR Tc bla(CTX-M-15)-harboring a bla(CTX-M-15) plasmid and a bla(OXA-1) plasmid. For in vivo experiments, mice were separately infected with each strain and treated with cefotaxime, amoxicillin, and clavulanate, alone or in combination, or imipenem, using therapeutic regimens reproducing time of free-drug concentrations above the MIC (fT≥MIC) values close to that obtained in humans. MICs of amoxicillin, cefotaxime, and imipenem were 4/>1,024, 0.125/1,024, and 0.5/0.5 mg/liter, for CFT073-RR and CFT073-RR Tc bla(CTX-M-15), respectively. The addition of 2 mg/liter of clavulanate (CLA) restored the susceptibility of CFT073-RR Tc bla(CTX-M-15) to CTX (MICs of the CTX-CLA combination, 0.125 mg/liter). The checkerboard dilution method and time-kill curves confirmed an in vitro synergy between amoxicillin-clavulanate and cefotaxime against CFT073-RR Tc bla(CTX-M-15). In vivo, this antibiotic combination was similarly active against both strains and as effective as imipenem. In conclusion, the cefotaxime and amoxicillin-clavulanate combination appear to be an effective, easy, and already available alternative to carbapenems for the treatment of UTI due to CTX-M-producing E. coli strains.

Topics: Amoxicillin-Potassium Clavulanate Combination; Animals; Anti-Bacterial Agents; beta-Lactam Resistance; beta-Lactamases; Cefotaxime; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Female; Gene Expression; Humans; Imipenem; Mice; Mice, Inbred CBA; Microbial Sensitivity Tests; Plasmids; Pyelonephritis; Urinary Tract Infections; Uropathogenic Escherichia coli

We evaluated the efficacy of NXL104, a novel β-lactamase inhibitor, in combination with ceftazidime (CAZ) in two murine infection models (septicemia and thigh infection). We chose two KPC-producing Klebsiella pneumoniae strains (VA-361 and VA-406) showing MICs of CAZ of ≥256 μg/ml. Septicemia was induced by the intraperitoneal injection of KPC-producing K. pneumoniae followed 30 min later by a single subcutaneous treatment with CAZ alone or CAZ-NXL104 in ratios of 2:1, 4:1, 8:1, and 16:1. In this model, the median effective doses for 50% (ED(50)) of the animals for CAZ alone versus VA-361 and VA-406 were 1,578 and 709 mg/kg of body weight, respectively. When combined with NXL104 at 2:1, 4:1, 8:1, and 16:1 ratios, the CAZ ED(50)s for VA-361 and VA-406 were reduced to 8.1 and 3.5 mg/kg, 15.1 and 3.8 mg/kg, 16.9 and 7.2 mg/kg, and 29.5 and 12.1 mg/kg, respectively. For thigh infection, neutropenia was induced by the intraperitoneal injection of cyclophosphamide at days -4 and -1 preinfection. Infection was established by the intramuscular injection of KPC-producing K. pneumoniae into the right thigh. Mice were treated 1.5 h postinfection with either CAZ alone or CAZ-NXL104 at constant ratios of 4:1. When thighs were removed at 24 h postinfection, a >2-log CFU reduction was observed for mice treated with CAZ-NXL104 at doses of ≥128:32 mg/kg. In contrast, CAZ doses of ≥1,024 mg/kg were unable to reduce the numbers of CFU. Despite resistance to CAZ and possessing a complex β-lactamase background, NXL104 combined with CAZ proved to be very effective in murine models of infection due to contemporary highly resistant KPC-producing K. pneumoniae isolates.

Topics: Animals; Anti-Bacterial Agents; Azabicyclo Compounds; Ceftazidime; Disease Models, Animal; Female; Klebsiella Infections; Klebsiella pneumoniae; Mice; Microbial Sensitivity Tests; Sepsis

Nonmammalian model systems of infection such as Galleria mellonella (caterpillars of the greater wax moth) have significant logistical and ethical advantages over mammalian models. In this study, we utilize G. mellonella caterpillars to study host-pathogen interactions with the gram-negative organism Acinetobacter baumannii and determine the utility of this infection model to study antibacterial efficacy. After infecting G. mellonella caterpillars with a reference A. baumannii strain, we observed that the rate of G. mellonella killing was dependent on the infection inoculum and the incubation temperature postinfection, with greater killing at 37 degrees C than at 30 degrees C (P = 0.01). A. baumannii strains caused greater killing than the less-pathogenic species Acinetobacter baylyi and Acinetobacter lwoffii (P < 0.001). Community-acquired A. baumannii caused greater killing than a reference hospital-acquired strain (P < 0.01). Reduced levels of production of the quorum-sensing molecule 3-hydroxy-C(12)-homoserine lactone caused no change in A. baumannii virulence against G. mellonella. Treatment of a lethal A. baumannii infection with antibiotics that had in vitro activity against the infecting A. baumannii strain significantly prolonged the survival of G. mellonella caterpillars compared with treatment with antibiotics to which the bacteria were resistant. G. mellonella is a relatively simple, nonmammalian model system that can be used to facilitate the in vivo study of host-pathogen interactions in A. baumannii and the efficacy of antibacterial agents.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Animals; Disease Models, Animal; Host-Pathogen Interactions; Moths; Quorum Sensing; Virulence

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

Vibrio vulnificus causes primary bacteremia and necrotizing wound infection, leading to high morbidity and mortality in humans. This study aimed to evaluate the antimicrobial effect of cefotaxime and minocycline on proinflammatory cytokine levels in a murine model of V. vulnificus infection.. We investigated the dynamics of proinflammatory cytokines and their modulation by antimicrobial agents using a murine model of V. vulnificus infection. The change in cytokine levels was followed over a time course to identify the antimicrobial activity of the drugs against V. vulnificus. BALB/c female mice were challenged with an intraperitoneal infection using a clinical invasive isolate of Vv05191, and their cytokine levels were assayed over various time points.. Serum levels of tumor necrosis factor-alpha, interleukin (IL)-1 beta, and IL-6 post-infection were found to be inoculum dose-dependent and positively correlated to the subsequent fatality rate in the infected mice. With an inoculum of 6.6 x 10(6) colony-forming units and intraperitoneal administration of cefotaxime, minocycline, or both, the serum and peritoneal fluid cytokine levels increased and then declined gradually. Comparison of the 3 antimicrobial regimens revealed that the magnitude of reduction in cytokine levels was greatest in mice treated with cefotaxime-minocycline combination. Moreover, the peritoneal fluid cytokine level in the combination group was significantly lower than that in the groups treated with minocycline or cefotaxime alone.. The current results support the superiority of the combination therapy in treating invasive V. vulnificus infections.

Topics: Animals; Anti-Bacterial Agents; Ascitic Fluid; Cefotaxime; Cytokines; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Female; Mice; Mice, Inbred BALB C; Minocycline; Survival Analysis; Vibrio Infections; Vibrio vulnificus

Antibiotic resistance continues to reduce the number of available antibiotics, increasing the need for novel antibacterial drugs. Since the seminal work of Sir Alexander Fleming, antibiotic identification has been based exclusively on the inhibition of bacterial growth in vitro. Recently, inhibitors of bacterial virulence which interfere with bacterial pathogenesis mechanisms have been proposed as an alternative to antibiotics, and a few were discovered using assays targeting specific virulence mechanisms. Here we designed a simple surrogate host model for the measurement of virulence and systematic discovery of anti-virulence molecules, based on the interaction of Tetrahymena pyriformis and Klebsiella pneumoniae cells. We screened a library of small molecules and identified several inhibitors of virulence. In a mouse pneumonia model we confirmed that an anti-virulence molecule displayed antibacterial activity against Klebsiella pneumoniae and Pseudomonas aeruginosa, by reducing dramatically the bacterial load in the lungs. This molecule did not inhibit bacterial growth in vitro but prevented biosynthesis of the Klebsiella capsule and lipopolysaccharides, a key requirement for virulence. Our results demonstrate that anti-virulence molecules represent an alternative to antibiotics and those can be discovered using non-animal host models.

Topics: Animals; Anti-Bacterial Agents; Bacteria; Cefotaxime; Cefpodoxime; Ceftizoxime; Cyclophosphamide; Disease Models, Animal; Female; Klebsiella Infections; Klebsiella pneumoniae; Lung; Mice; Mice, Inbred BALB C; Molecular Structure; Mutation; Neutropenia; Pseudomonas aeruginosa; Tetrahymena pyriformis; Time Factors; Triazines; Virulence

A dose-ranging study to investigate the in vivo effects of the presence of specific antibodies on the efficacy of beta-lactam treatment of sepsis caused by Streptococcus pneumoniae (non-beta-lactam-susceptible serotype 6B isolate) was performed with a BALB/c mouse model. Hyperimmune serum was obtained from mice immunized with the heat-inactivated strain. The rate of mortality was 100% in nontreated animals in the absence of specific antibodies. A single injection of a one-half or one-quarter dilution of hyperimmune serum produced 60 to 40% survival rates. In the absence of specific antibodies, the minimal effective doses of amoxicillin and cefotaxime that produced survival rates of 100 and 80% were 25 and 50 mg/kg of body weight (three times a day for up to six doses), respectively. These doses produced times that the levels in serum remained above the MIC (deltaT > MICs) approximately 30% of the dosing interval. When specific antibodies were present (by administration of a one-half or one-quarter dilution of hyperimmune serum), the minimal effective doses of the antibiotics were 3.12 and 6.25 mg/kg ( approximately 8 times lower), with the deltaT > MICs being approximately 3 and 5% of the dosing interval for amoxicillin and cefotaxime, respectively. This in vivo combined pharmacodynamic effect offers possibilities that can be used to address penicillin resistance.

Topics: Amoxicillin; Animals; Antibodies, Bacterial; Antibody Specificity; beta-Lactams; Cefotaxime; Disease Models, Animal; Humans; Immune Sera; Mice; Mice, Inbred BALB C; Pneumococcal Infections; Sepsis; Streptococcus pneumoniae; Treatment Outcome

In this paper, the first robust experimental evidence of in vitro and in vivo concentration-dependent selection of low-level antibiotic-resistant genetic variants is described. The work is based on the study of an asymmetric competition assay with pairs of isogenic Escherichia coli strains, differing only (apart from a neutral chromosomal marker) in a single amino acid replacement in a plasmid-mediated TEM-1 beta-lactamase enzyme, which results in the new TEM-12 beta-lactamase. The mixture was challenged by different antibiotic concentrations, both in vitro and in the animal model, and the selective process of the variant population was carefully monitored. A mathematical model was constructed to test the hypothesis that measured growth and killing rates of the individual TEM variants at different antibiotic concentrations could be used to predict quantitatively the strength of selection for TEM-12 observed in competition experiments at these different concentrations.

Topics: Animals; beta-Lactam Resistance; beta-Lactamases; Cefotaxime; Cell Division; Cephalosporins; Disease Models, Animal; Dose-Response Relationship, Drug; Escherichia coli; Mice; Models, Biological; Phenotype; Porins; Selection, Genetic

Preliminary estimation of virulence in some antibiotic resistant mutants of Legionella pneumophila, Philadelphia 1 in various models of infection revealed its decrease in the mutants resistant to azlocillin, cefotaxime, fluoroquinolone LIB-80, neamine and streptomycin. Detailed investigation of the neamine resistant mutants showed that in relation to streptomycin susceptibility such mutants could be divided into 3 classes: susceptible to streptomycin, resistant to high concentrations of streptomycin and resistant to moderate concentrations of streptomycin. Part of mutants Nea(r)Strr and Nea(r)Strr500 and all mutants Nea(r)Strr100 proved to be less virulent with respect to guinea pigs and chick embryos. The study of the spectinomycin resistant mutants of Legionella spp. did not reveal any changes in the virulence which made it possible to suggest that the influence of the mutations in the ribosomal protein genes determining resistance to streptomycin and neamine on virulence of L. pneumophila was based on the interdependence of the mutant effect on the suppression and the influence on the virulence detected by us in S. flexneri, Y. pseudotuberculosis, L. monocytogenes and F. tularensis. The Legionella mutants Nea(r)Strr100 were characterized by significant protective activity and protected immunized guinea pigs when tested in a model of their aerogenic infection.

Topics: Animals; Anti-Bacterial Agents; Azlocillin; Cefotaxime; Chick Embryo; Disease Models, Animal; Drug Resistance, Microbial; Guinea Pigs; Legionella pneumophila; Legionnaires' Disease; Mutation; Neomycin; Streptomycin

To investigate the influence of different classes and doses of antibiotics on endotoxin release in gram-negative infection in a rat model of intra- abdominal infection.. Immediately after intraperitoneal inoculation of Escherichia coli (5 x 10(7) colony-forming units/kg), anesthetized Wistar rats were treated with a single intravenous dose of an antimicrobial agent: cefotaxime (40 mg/kg), ciprofloxacin (3 mg/kg or 6 mg/kg), imipenem (7 mg/kg or 14 mg/kg), or gentamicin (5 mg/kg). An untreated control group received 0.9% sodium chloride instead of antibiotic. Plasma endotoxin activity, blood bacteria count, and mean arterial pressure were monitored at 60-minute intervals for 5 hours. At the end of the experiment, lavage was performed to determine the bacteria count in the peritoneal cavity.. In the untreated group, the blood bacteria count increased rapidly. Five hours after therapy, the plasma endotoxin activity in the cefotaxime group was higher by a factor of 3.6 than in the untreated group. Compared with the cefotaxime group, endotoxin activity was approximately 26% lower in the ciprofloxacin (3 mg/kg) group, 35% lower in the imipenem groups, and 38% lower in the gentamicin group. The lowest endotoxin levels were in the high-dose ciprofloxacin group. Bacteria counts in the peritoneal cavity were lowest in the gentamicin and high-dose ciprofloxacin groups. Except in the high-dose ciprofloxacin group, the endotoxin increase in the therapy groups was associated with a significant (P < .05) decrease in mean arterial pressure.. In the early phase of therapy, antibiotic-induced endotoxin release is influenced by the mode of action of the agent class. This is not the sole influence in every class. With quinolones, this effect is also influenced considerably by dosage, ie, by pharmacodynamics.

Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Bacteremia; Blood Pressure; Cefotaxime; Cephalosporins; Ciprofloxacin; Colony Count, Microbial; Disease Models, Animal; Endotoxins; Escherichia coli; Escherichia coli Infections; Gentamicins; Imipenem; Male; Peritoneal Diseases; Peritoneum; Rats; Rats, Wistar; Thienamycins

The present study confirms that CBA/J mice are susceptible to several clinical isolates of Streptococcus pneumoniae, including four of five penicillin-susceptible and all five penicillin-resistant strains tested, thus providing the first noncompromised animal model for penicillin-resistant S. pneumoniae pneumonia. In this model, doses of penicillin G of 0.6 mg/kg of body weight given six times at 1-h intervals produced effective pulmonary clearance of a penicillin-susceptible strain (penicillin G MIC, 0.015 microgram/ml), while doses of 40 mg/kg given six times at 1-h intervals were required to clear a penicillin-resistant strain (penicillin G MIC, 1 microgram/ml). Imipenem (MIC, 0.25 microgram/ml) was the most active antibiotic tested against the penicillin-resistant strain, with a calculated dose of 0.42 mg/kg given six times at 1-h intervals, resulting in a 2-log decrease in the number of pulmonary bacteria. Comparable effects were seen with vancomycin (MIC, 0.5 microgram/ml), cefotaxime (MIC, 0.5 microgram/ml), and penicillin G at doses of 3.3, 5.5, and 31.0 mg/kg given six times at 1-h intervals, respectively. The pharmacokinetic profile of vancomycin in infected lungs was superior to those of the other antibiotics, especially in regard to the elimination half-life (215.4 min for vancomycin versus 15.0, 14.5, and 14.5 min for penicillin G, cefotaxime, and imipenem, respectively). Both imipenem and vancomycin allowed 90% survival when 40-mg/kg doses were administered twice a day beginning 5 days after infection. Survival rates with penicillin G (160-mg/kg doses) and cefotaxime (40-mg/kg doses) were 40 and 30%, respectively, while no saline-treated mice survived. The present study shows that the CBA/J mouse pneumonia model may be useful for evaluating antibiotic efficacies against penicillin-resistant pneumococcal pneumonia in immunocompetent individuals. Our data suggest that imipenem and vancomycin may be the most active agents against penicillin-resistant S. pneumoniae pneumonia.

Topics: Animals; Anti-Bacterial Agents; Cefotaxime; Disease Models, Animal; Imipenem; Lung; Male; Mice; Mice, Inbred CBA; Mice, Inbred ICR; Microbial Sensitivity Tests; Penicillin G; Penicillin Resistance; Pneumonia, Pneumococcal; Species Specificity; Streptococcus pneumoniae; Vancomycin

In an attempt to determine the susceptibility breakpoints for amoxycillin, co-amoxiclav and cefotaxime in pneumococcal pneumonia, a neutropenic mouse model was established and tested with two strains having different susceptibility to penicillins and cefotaxime. With a penicillin-sensitive strain (MIC/MBC = 0.01/0.01 mg/L) the minimum dosage tested achieving significant cure was 2 mg/kg for amoxycillin, co-amoxiclav and cefotaxime. For the penicillin-insensitive strain (MIC/MBC = 1/2 mg/L), the minimum dosage tested giving significant cure was 50 mg/kg for amoxycillin and co-amoxiclav but 100 mg/kg for cefotaxime. Our results support the belief that MICs of amoxycillin, co-amoxiclav and cefotaxime for pneumococcal strains of < or = 0.5 or < or = 1 mg/L can be considered as clinically relevant susceptibility breakpoints.

Topics: Amoxicillin; Amoxicillin-Potassium Clavulanate Combination; Animals; Cefotaxime; Cephalosporins; Clavulanic Acids; Disease Models, Animal; Drug Therapy, Combination; Female; Mice; Microbial Sensitivity Tests; Penicillins; Pneumonia, Pneumococcal; Streptococcus pneumoniae

The purpose of this study was to develop a model of bacterial meningitis in young adult rats for assessing the efficacy of antimicrobial agents. Sixty 200- to 300-g male Sprague Dawley CD rats were inoculated intracisternally with 5.78 log10 CFU of a clinical isolate of Streptococcus pneumoniae in 5% hog gastric mucin. Inoculated rats were assigned to six groups containing 10 animals each. Group-1 rats served as controls and did not receive antibiotics. Rats of groups 2 to 4 received (subcutaneously every 12 h) cefotaxime (25, 6.25, and 1.56 mg/kg of body weight respectively). Rats of groups 5 and 6 received ampicillin (50 and 12.5 mg/kg respectively) and gentamicin (2.0 and 0.5 mg/kg respectively). Five additional Sprague Dawley CD rats were inoculated with only gastric hog mucin and were assigned to group 7. At postinoculation day 4 all animals were euthanized. Cerebral spinal fluid was collected for culturing. Brains were harvested for histologic examination and culturing. Untreated, infected control (group-1) animals were culture-positive for S. pneumoniae in the brain and cerebral spinal fluid. Of the antibiotic regimens evaluated, only cefotaxime (25 mg/kg) eradicated bacteria from the cerebral spinal fluid and brain. Cefotaxime at 25 or 6.25 mg/kg significantly (P < or = 0.05) decreased the bacterial burden of S. pneumoniae, whereas cefotaxime at 1.56 mg/kg and ampicillin/gentamicin combinations did not. There was histopathological evidence of subacute meningitis in infected rats. No meningitis was observed in rats receiving 25 mg of cefotaxime/kg. This model demonstrates the ability to induce bacterial meningitis with S. pneumoniae in adult rats and the ability to clear infection in 90 to 100% of the animals by administration of cefotaxime at dosages of 6.25 and 25 mg/kg given subcutaneously every 12 h.

Topics: Ampicillin; Animals; Anti-Bacterial Agents; Brain; Cefotaxime; Cerebrospinal Fluid; Disease Models, Animal; Gentamicins; Male; Meninges; Meningitis; Rats; Rats, Sprague-Dawley; Rodent Diseases; Rodentia; Streptococcus pneumoniae

We studied the antipneumococcal efficacy of cefotaxime and vancomycin alone and a combination of cefotaxime with various dosages of vancomycin in the treatment of prolonged (48 h) experimental fibrin clot infections in rabbits. A clinical pneumococcal strain for which MICs were 2, 0.5 and 0.5 mg/L of penicillin, cefotaxime and vancomycin respectively, was used in this study. Cefotaxime was given iv at a fixed dose of 50 mg/kg and vancomycin iv at 1, 2.5, 5, 10 or 20 mg/kg. Maximal concentrations in clots were (mean +/- S.D.): 2.1 +/- 0.9, 1.1 +/- 0.4, 1.9 +/- 1, 2.3 +/- 1.5, 3.6 +/- 0.4 and 4 +/- 0.3 mg/g, respectively. The mean half-lives of elimination from clots were 2.2 h for cefotaxime and 7 h for vancomycin. We observed the highest bacterial reductions for the highest doses of vancomycin with or without cefotaxime. The combination of intermediate doses of vancomycin with cefotaxime led to higher antibacterial effects than either monotherapy. The low dose of vancomycin gave no significant additional effect compared with cefotaxime alone. The times of regrowth were similar for cefotaxime and cefotaxime-vancomycin 1, and also for vancomycin 10 and vancomycin 20 with or without cefotaxime but were significantly delayed for the combination cefotaxime-vancomycin 2.5 and cefotaxime-vancomycin 5 as compared with vancomycin 2.5 and vancomycin 5. By using a multivariate analysis, we demonstrated that the most important parameters were Cmax (r = 0.43) and AUC (r = 0.58) for cefotaxime alone and Cmax (r = 0.70) for vancomycin alone; none of the tested parameters was found to be significantly correlated with the efficacy of the combinations of cefotaxime and vancomycin. From these findings, and under the experimental conditions used (i.e., relatively low concentrations of cefotaxime), we demonstrated that the in-vivo antibacterial efficacy of the combination of cefotaxime and vancomycin was higher than each monotherapy when the local concentrations of vancomycin were at least 1.9 mg/L.

Topics: Analysis of Variance; Animals; Cefotaxime; Disease Models, Animal; Drug Therapy, Combination; Fibrin; Half-Life; Microbial Sensitivity Tests; Penicillin Resistance; Pneumococcal Infections; Rabbits; Thrombosis; Treatment Outcome; Vancomycin

The MIC is the main microbiologic parameter used to predict the efficacies of antibiotics. However, it is well known that MICs may vary according to the inoculum size used (inoculum effect), especially with some beta-lactam antibiotics. In order to correlate the pharmacologic and microbiologic properties of some beta-lactams, an experimental model of intraperitoneal infection caused by Escherichia coli in nonneutropenic and neutro-penic mice was developed. The animals were treated with three different doses of either ampicillin, piperacillin, aztreonam, cefazolin, or cefotaxime. The linear regression analysis obtained in our model shows a better correlation between in vitro activity and efficacy when the MICs considered were those obtained with a large inoculum (ca. 1 x 10(8) CFU/ml) instead of the standard inoculum (5 x 10(5) CFU/ml). The correlations for the MICs obtained with the large inoculum were 0.78 for log2 maximum concentration of drug in serum (Cmax)/ MIC, 0.72 the time that the concentrations exceeded the MIC, and 0.79 for log2 area under the serum concentration-time curve (AUC)/MIC at 24 h in nonneutropenic mice. The corresponding values in neutropenic mice, also for the MICs obtained with the large inoculum, were 0.54, 0.68, and 0.64, respectively, at 24 h. A good correlation was also obtained for the same parameters in nonneutropenic mice at 48 h. The values of Cmax, AUC, and the time that the concentrations exceeded the MIC were parallel among the antibiotics studied, and our study confirms that the time that the levels in serum exceed the MIC is a significant parameter determining the efficacies of beta-lactam antibiotics, but the correlation is much better when the MICs obtained with the large inoculum instead of those obtained with the standard (low) inoculum are considered.

Topics: Ampicillin; Animals; Anti-Bacterial Agents; Aztreonam; Cefazolin; Cefotaxime; Disease Models, Animal; Escherichia coli Infections; Male; Mice; Peritoneal Diseases; Piperacillin

Acute respiratory infection with penicillin-insensitive Streptococcus pneumoniae (MIC and MBC, 1 and 2 micrograms/ml, respectively) was established in guinea pigs. Intratracheal instillation of 0.5 ml of an overnight culture of S. pneumoniae concentrated 25 times (approximately 3 x 10(9) CFU) induced a bacteremic and fatal pneumonia in > 85% of untreated animals within 46 h, with a mean +/- standard deviation bacterial count of 8.83 +/- 1.11 log10 CFU in lung homogenates. This model was used to evaluate the efficacies of two doses each of amoxicillin, cefotaxime, and meropenem given 1 h after bacterial inoculation. The antibiotics were given at 8-h intervals for up to a total of four injections. The dose of 50 mg of any antibiotic per kg of body weight gave 66.6% survival, compared with 5.05% survival for untreated control animals (P < 0.001). A dose of 200 mg/kg gave a survival rate of 77.8% for meropenem and 83.3% for amoxicillin and cefotaxime, while survival for untreated controls was 11.1% (P < 0.001). Although antibiotic treatment decreased mortality compared with that in untreated controls, the antibiotics contributed to a high early (less than 9 h after bacterial inoculation) mortality, being 53.5% compared with only 6.06% for the untreated controls (P < 0.001). Quantitative cultures of the lungs of animals that died during the 46-h observation period or that were killed after this time showed a significant reduction in the numbers of organisms among treated animals compared with numbers among the control animals (P < 0.001). The described model is an appropriate system for evaluating antibiotic efficacy in invasive pulmonary infection caused by penicillin-insensitive S. pneumoniae.

Topics: Amoxicillin; Animals; Cefotaxime; Cephalosporins; Colony Count, Microbial; Disease Models, Animal; Female; Guinea Pigs; Lung; Meropenem; Penicillin Resistance; Penicillins; Pneumonia, Pneumococcal; Streptococcus pneumoniae; Thienamycins

We previously demonstrated the efficacy of ceftriaxone (CRO), at 50 mg/kg of body weight every 12 h, against a highly penicillin-resistant (MIC, 4 micrograms/ml) Streptococcus pneumoniae strain with low-level resistance to CRO (MIC, 0.5 microgram/ml) in a leukopenic-mouse pneumonia model (P. Moine, E. Vallée, E. Azoulay-Dupuis, P. Bourget, J.-P. Bédos, J. Bauchet, and J.-J. Pocidalo, Antimicrob. Agents Chemother. 38:1953-1958, 1994). In the present study, we assessed the activity of CRO versus those of cefotaxime (CTX) and amoxicillin (AMO) against two highly penicillin- and cephalosporin-resistant S. pneumoniae strains (P40422 and P40984) (MICs of 2 and 8 for penicillin, 2 and 4 for AMO, and 4 and 8 for CRO or CTX, respectively). Against both strains, a greater than an 80% cumulative survival rate was observed with CRO at a dose of 100 or 200 mg/kg every 12 h (dose/MIC ratio, 25). With CTX, a high dosage of 400 mg/kg (dose/MIC ratio, 100 or 50) administered every 8 h (TID) was needed to protect 66 and 75% of the animals, respectively, with no statistically significant differences versus CRO. Against the P40422 strain, CRO (100 mg/kg) produced the greatest bactericidal effect, from the 8th to the 24th hour after a single injection (1.8-log-unit reduction over 24 h), and the fastest bacterial pulmonary clearance during treatment; with CTX, only multiple injections at a high dosage, i.e., 400 mg/kg TID, demonstrated a significant bactericidal effect. AMO in a high dosage, 400 mg/kg (dose/MIC ratio, 200) TID, showed good activity only against the P40422 strain. Despite the identical MICs of CTX and CRO, the longer time (3.6 to 4.6 h) that serum CRO concentrations remained above the MICs for the pathogens at a dose of 100 mg/kg resulted in greater efficacy versus CTX against highly penicillin- and cephalosporin-resistant S. pneumoniae strains.

Topics: Amoxicillin; Animals; Cefotaxime; Ceftriaxone; Cephalosporin Resistance; Cephalosporins; Disease Models, Animal; Female; Lung; Mice; Microbial Sensitivity Tests; Penicillin Resistance; Penicillins; Pneumonia, Pneumococcal; Streptococcus pneumoniae

The authors test antibiotic strategies aimed at either mitigating bacterial translocation from the gut or delivering antibiotics specifically concentrated by the pancreas for prevention of early secondary infection after acute necrotizing pancreatitis.. Infection currently is the principal cause of death after severe pancreatitis. The authors have shown that the risk of bacterial infection correlates directly with the degree of tissue injury in a rodent model of pancreatitis. Bacteria most likely arrive by translocation from the colon.. Severe acute necrotizing pancreatitis was induced in rats by a combination of low-dose controlled intraductal infusion of glycodeoxycholic acid superimposed on intravenous cerulein hyperstimulation. At 6 hours, animals were randomly allocated to five treatment groups: controls, selective gut decontamination (oral antibiotics and cefotaxime), oral antibiotics alone, cefotaxime alone, or imipenem. At 96 hours, surviving animals were killed for quantitative bacterial study of the cecum, pancreas, and kidney.. The 96-hour mortality (35%) was unaffected by any treatment regimen. Cecal gram-negative bacteria were significantly reduced only by the oral antibiotics. Pancreatic infection was significantly reduced by full-gut decontamination and by imipenem, but not by oral antibiotics or by cefotaxime alone. Renal infection was reduced by both intravenous antibiotics.. Early pancreatic infection after acute necrotizing pancreatitis can be reduced with a full-gut decontamination regimen or with an antibiotic concentrated by the pancreas (imipenem) but not by unconcentrated antibiotics of similar spectrum (cefotaxime) or by oral antibiotics alone. These findings suggest that 1) both direct bacterial translocation from the gut and hematogenous seeding interplay in pancreatic infection while hematogenous seeding is dominant at extrapancreatic sites and 2) imipenem may be useful in clinical pancreatitis.

Topics: Acute Disease; Administration, Oral; Amphotericin B; Animals; Bacteria; Bacterial Infections; Bacterial Physiological Phenomena; Cecal Diseases; Cefotaxime; Colistin; Disease Models, Animal; Drug Therapy, Combination; Imipenem; Injections, Intravenous; Kidney Diseases; Male; Necrosis; Pancreas; Pancreatic Diseases; Pancreatitis; Rats; Rats, Sprague-Dawley; Survival Rate; Tobramycin

An investigation examined the efficacy of antibiotics in a novel feline model of pancreatic infection in acute pancreatitis. Acute pancreatitis was induced in cats using an established technique. In control animals (no pancreatitis) and cats with pancreatitis, Escherichia coli (10(4) in 0.1 ml) was placed in the pancreatic duct. Reoperation was performed after 24 h in six controls and six cats with pancreatitis. E. coli was cultured from the pancreas in five control animals and five cats with pancreatitis. Reoperation was performed after 1 week in ten controls, in 11 cats with pancreatitis and in nine with pancreatitis that were treated with cefotaxime (50 mg/kg intramuscularly three times daily) started 12 h after the induction of pancreatitis and administration of E. coli. Pancreatic infection developed in eight cats with pancreatitis compared with none of the cefotaxime-treated animals and none of the controls (P < 0.05). Cefotaxime reached bactericidal levels in pancreatic tissue and juice. In conclusion, ductal administration of E. coli caused pancreatic infection only in cats with acute pancreatitis. Early administration of an appropriate antibiotic was effective in treating pancreatic infection in acute pancreatitis.

Topics: Acute Disease; Animals; Cats; Cefotaxime; Disease Models, Animal; Escherichia coli; Escherichia coli Infections; Opportunistic Infections; Pancreas; Pancreatitis

A group of three-month old, male Crl:CD1(ICR) BR mice, was fed chow containing Candida albicans, while another group of the same type of mice was fed regular chow. Both groups were treated subsequently with either antibiotics or normal saline for 10 days. Stool cultures were performed before treatment, at the end of treatment, and one week after the end of treatment, to determine the level of colonization of the gastrointestinal tract by the yeast. The stools of mice fed Candida and treated with antibiotics had substantially higher Candida counts than control mice fed C. albicans and treated with saline. The highest concentrations of the yeast were observed in the stools of mice treated with cefotaxime as compared to those of mice treated with pefloxacin, amikacin and amoxicillin. No Candida was found in the stools of mice fed regular chow and treated with antibiotics or saline. Dissemination of Candida was not observed in the visceral organs of any mouse.

Topics: Amikacin; Amoxicillin; Animals; Anti-Bacterial Agents; Candida albicans; Candidiasis; Cefotaxime; Digestive System; Disease Models, Animal; Feces; Gastrointestinal Diseases; Male; Mice; Mice, Inbred ICR; Pefloxacin

The in vivo synergistic effect of cefodizime (CDZM) in combination with minocycline (MINO) against methicillin-resistant Staphylococcus aureus (MRSA) was investigated. A study of fractional effective dose (FED) index showed that either synergistic or additive effect was observed between CDZM and MINO. The postantibiotic effect (PAE) of MINO was not altered by the addition of CDZM. However, a strong synergistic bactericidal effect of CDZM and MINO against MRSA CT-18 was observed for more than 14 hours in the presence of immunocompromised tumour bearing murine polymorphonuclear leukocytes (PMN). These results suggest that the strong therapeutic efficacy of CDZM in combination with MINO was caused by synergistic bactericidal effect of the 2 drugs in the presence of PMN.

Topics: Animals; Carcinoma, Ehrlich Tumor; Cefotaxime; Disease Models, Animal; Drug Therapy, Combination; In Vitro Techniques; Male; Methicillin Resistance; Mice; Mice, Inbred Strains; Microbial Sensitivity Tests; Minocycline; Neutrophils; Serotyping; Staphylococcus aureus

An experimental model in Wistar rats, of osteomyelitis caused by Escherichia coli, was used to evaluate the efficacy of cefotaxime in two treatment regimens of different durations. Four groups of rats were set up: a group of rats receiving short-term treatment (14 days) with subcutaneous cefotaxime (100 mg bd), killed after 56 days; a control group receiving no treatment, killed after 56 days; a group of rats undergoing long-term treatment (28 days) with subcutaneous cefotaxime as above, killed after 70 days and a control group of rats receiving no treatment, killed after 70 days. Analysis of histopathological and microbiological findings revealed significantly better results in the long-term treatment group. No side-effects were observed during treatment or afterwards.

Topics: Animals; Cefotaxime; Chronic Disease; Disease Models, Animal; Escherichia coli Infections; Female; Osteomyelitis; Rats; Rats, Inbred Strains

An experimental model of infected subcutaneous fibrin clots in rabbits was used to study the synergism between cefotaxime and fosfomycin in infection with methicillin and gentamicin resistant Staphylococcus aureus (MGRSA), and to determine the efficacy of a simplified schedule of administration. The bactericidal activity of cefotaxime and fosfomycin against MGRSA was investigated giving the drugs in one full or two divided doses either alone or in combination. The pharmacokinetics of the drugs were correlated with the antibacterial efficacy obtained over 12 hours of treatment. The results confirmed that the combination of cefotaxime and fosfomycin is highly synergistic in experimental MGRSA infection. Higher bactericidal activity was obtained with a regimen of 6-hourly drug administration which resulted in persistent levels of both drugs in serum as well as at the site of infection.

Topics: Analysis of Variance; Animals; Cefotaxime; Disease Models, Animal; Drug Administration Schedule; Drug Resistance, Microbial; Drug Synergism; Drug Therapy, Combination; Fosfomycin; Gentamicins; Male; Methicillin; Penicillin Resistance; Rabbits; Staphylococcal Infections; Staphylococcus aureus

Serum cefotaxime and desacetylcefotaxime concentrations and their tissue concentrations in the kidney were determined at 30 minutes after cefotaxime (80 mg/kg) bolus intravenous infusion in rabbits when the urinary tract was obstructed. Serum concentration was highest in bilateral ureteral obstruction (BUO) animals (142.1 +/- 25.4 mg/L), followed in order by unilateral ureteral obstruction (UUO) animals (92.6 +/- 10.4 mg/L) and sham-operated animals (50.4 +/- 9.9 mg/L). Both serum cefotaxime and desacetylcefotaxime concentrations were highly correlated with serum creatinine levels. Conversely, the renal tissue/serum concentration ratio of cefotaxime and its metabolite was lowest in BUO animals, which was in accordance with physiological evidence that renal blood flow was reduced in BUO. Indomethacin pretreatment exaggerated cefotaxime and desacetylcefotaxime accumulation in the obstructed kidney of the UUO model, indicating that this drug inhibits renal elimination of cefotaxime when urinary tract obstruction exists.

Topics: Animals; Cefotaxime; Disease Models, Animal; Indomethacin; Kidney; Male; Rabbits; Ureteral Obstruction; Urinary Tract Infections

In various infection models with the pathogenic yeast Candida albicans, Cefodizime influences the development of the infection. Although it does not exhibit any fungicidal or fungistatic action it decreases the number of yeast cells or prolonges survival.

Topics: Animals; Candidiasis; Cefotaxime; Disease Models, Animal; Female; Immune System; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Rats

Experience with the use of first-generation cephalosporins in bacterial meningitis has been disappointing; low concentrations were obtained in the cerebrospinal fluid, and therapeutic failures were encountered. Of the second-generation cephalosporins cefamandole, cefuroxime, and cefoxitin, only cefuroxime has proved efficacy in meningitis caused by meningococci, pneumococci, or Hemophilus influenzae. The third-generation cephalosporins offer new advantages in the treatment of meningitis because they are active at the cerebrospinal fluid concentrations obtainable. Cefotaxime has produced high cure rates in patients with meningitis caused by meningococci, pneumococci, or H. influenzae. Several controlled comparative studies indicate that ceftriaxone is as effective as conventional treatment in therapy for neonatal or childhood meningitis caused by Streptococcus agalactiae, Escherichia coli, or H. influenzae. Moxalactam has been found in uncontrolled studies to be effective when the cause was enteric gram-negative bacilli. Ceftazidime is a new cephalosporin with a high degree of beta-lactamase stability and a broad antibacterial spectrum, which includes Pseudomonas aeruginosa that enters the cerebrospinal fluid. Data from 29 patients who received ceftazidime as monotherapy for bacterial meningitis showed an overall cure or improvement rate of 75.9 percent. Therapy failed in three patients with meningitis caused by gram-positive organisms (Staphylococcus aureus, S. epidermidis, S. agalactiae), and in three with gram-negative organisms. Of 14 patients with Pseudomonas meningitis, 11 showed a cure, as did six of six patients with meningitis caused by Enterobacter, Serratia, or Acinetobacter. More, preferably controlled, studies of the efficacy of ceftazidime in the treatment of meningitis should be undertaken.

Topics: Adult; Animals; Bacterial Infections; Cefoperazone; Cefotaxime; Ceftazidime; Ceftriaxone; Cephalosporins; Disease Models, Animal; Humans; Meningitis

In the E. coli pyelonephritis, induced in female Wistar rats by retrograde infection (high pressure reflux), we investigated the influence of 1) the time of commencement of therapy, 2) the renal bacterial counts, i.e. the inflammatory activity of the pyelonephritis after endovesical instillation of cultures with different bacterial concentrations, and 3) the level of infection resistance of the experimental animal strain on the therapeutic response of the model infection with single doses of cefoxitin (150 mg/ml) and cefotaxime (5 mg/ml). Early commencement of therapy post inoculation was therapeutically advantageous provided the intrarenal multiplication of the infective organisms was not delayed or the initial bacterial concentrations were not too high. The mild form of pyelonephritis with lower renal bacterial concentrations and poor inflammatory activity after endovesical instillation of a low inoculum (10(4) cfu/ml) was less amenable to treatment than the inflammatory active pyelonephritis with high renal bacterial counts, using a high inoculum (10(7) cfu/ml). High renal bacterial counts after retrograde inoculation of an E. coli culture of 10(8) cfu/ml resulted in significant reduction of bacterial counts 48, 72 and 96 h post infectionem, with i.m. application of cefoxitin 12 h prior. For Wistar rat strain Bor:WIST, which showed a stronger infection resistance with lower renal bacterial concentrations and a stronger tendency to spontaneous healing, application of a single dose of cefotaxime (5 mg/ml) was therapeutically ineffective, whereas, in contrast, with Han: WIST rats the acute phase of E. coli pyelonephritis could be treated effectively.

Topics: Animals; Cefotaxime; Cefoxitin; Disease Models, Animal; Escherichia coli; Escherichia coli Infections; Female; Kidney; Pyelonephritis; Rats; Rats, Inbred Strains

The efficacy of beta-lactam antibiotics and amikacin alone and in various combinations against Pseudomonas aeruginosa was studied in a rabbit model simulating a closed-space infection in a locally neutropenic site. Six strains of P. aeruginosa were studied in semipermeable chambers placed subcutaneously in rabbits. Therapy was begun 4 h after inoculation of 5 X 10(4) CFU of bacteria per ml of pooled rabbit serum into the chambers. Antibiotics were administered intramuscularly every 6 h for 16 doses. Quantitative bacteriology was measured at the start of therapy and at 20, 44, and 92 h thereafter. Antibiotic concentrations were measured in blood and chamber fluid. Results were compared with in vitro tests of susceptibility and synergy. No single-agent therapy eradicated any of the six test organisms. Azlocillin (100 mg/kg per dose) plus amikacin (20 mg/kg per dose) eliminated five of six organisms by 92 h, and ceftizoxime (100 mg/kg per dose) plus amikacin (20 mg/kg per dose) eliminated three of six test strains. Azlocillin plus ceftizoxime (each 100 mg/kg per dose) failed to eliminate any of the six strains. To eliminate P. aeruginosa in this model, two drugs were required, with one being an aminoglycoside. In vitro susceptibility tests of synergy were predictive of successful therapy whenever the antibiotic concentrations (free and total) at the infection site exceeded the MBC for both the aminoglycoside alone and the beta-lactam when tested in combination with amikacin.

Topics: Agranulocytosis; Amikacin; Animals; Anti-Bacterial Agents; Azlocillin; Cefotaxime; Cefoxitin; Ceftizoxime; Disease Models, Animal; Drug Combinations; Female; Hydrogen-Ion Concentration; Kanamycin; Microbial Sensitivity Tests; Neutropenia; Penicillins; Protein Binding; Pseudomonas Infections; Rabbits

Plasma levels and distribution in pulmonary and bronchial tissues of CTM following injection into the jugular vein were investigated in rabbits with experimental pleuritis or pneumonitis as well as in normal rabbits. The experiments also included the assessment of the effect of concomitant administration of serratiopeptidase (TSP). The pneumonitis + TSP group, pleuritis group and pleuritis + TSP group showed a tendency to delayed dissipation of CTM from the plasma, as compared with controls. The CTM concentrations in tissues from the apical region of upper lobe (L1), lateral region of middle lobe (L2) and diaphragmatic region of lower lobe (L3) 30 minutes after injection did not differ significantly between the control and the TSP group, pleuritis group or pleuritis + TSP group. In the pneumonitis group, the tissue CTM concentrations at all 3 sites (L1, L2, L3) were lower than those in the control group. They were increased by the concomitant administration of TSP, with statistical significance of increase in regions L2 and L3. Thirty minutes after the injection of CTM, the pneumonitis group and pneumonitis + TSP group displayed essentially comparable CTM levels in pleural fluid, whereas the CTM concentrations in the pleural fluid were prone to be increased in the pleuritis + TSP group as comparing with the pleuritis group. CTM levels in the tissues of trachea (B0), right and left main bronchi (B1) and lobar bronchi (B2) 30 minutes after the injection did not show any significant difference between control and TSP-treated normal groups. CTM concentrations tended to be increased, yet not significantly, in all these regions in the rabbits with pleuritis administered TSP, compared to those without TSP.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cefotaxime; Cefotiam; Disease Models, Animal; Lung; Male; Peptide Hydrolases; Pleurisy; Pneumonia; Rabbits; Tissue Distribution; Trachea

Topics: Animals; Bacterial Infections; Bacteroides Infections; Cefotaxime; Ceftizoxime; Disease Models, Animal; Male; Mice; Neutropenia; Sepsis; Wound Infection

The therapeutic efficacy of ceftriaxone and gentamicin was investigated in a foreign body induced abscess model in the rat by implanting a dialysis tube contaminated with Klebsiella pneumoniae into the subcutaneous tissue. Animals were treated for four days with ceftriaxone, gentamicin, and their combination starting immediately following or 48 h after the implantation. Peak free ceftriaxone and gentamicin abscess fluid levels were 4.3 and 2.6 mcg/ml, which were 7.3% and 37.5% of peak blood levels respectively. Both agents persisted longer in abscess fluid than in blood. Ceftriaxone inhibited the development of abscess formation when administered shortly after the implantation of the contaminated foreign body whereas gentamicin alone was without beneficial effect. When administered after 48 h ceftriaxone was less effective than immediately after implantation and gentamicin was again without any therapeutic effect. The effect of the combination of ceftriaxone and gentamicin was slightly better than ceftriaxone alone. Low oxygen tension may be an explanation for the lack of bactericidal effect of gentamicin. Ceftriaxone may be more suitable for the therapy of closed space infections caused by susceptible microorganisms than gentamicin.

Topics: Abscess; Animals; Cefotaxime; Ceftriaxone; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Therapy, Combination; Female; Gentamicins; Kinetics; Klebsiella Infections; Klebsiella pneumoniae; Male; Rats; Rats, Inbred Strains