Evaluation of combination chemotherapy in a lightly anesthetized animal model of Pseudomonas pneumonia.

Gram-negative bacillary pneumonia is a major cause of morbidity and mortality in hospitalized patients. The use of synergistic combinations of aminoglycosides and beta-lactams for therapy of this infection has been recommended but remains controversial. We designed a new model of Pseudomonas pneumonia in a lightly sedated guinea pig by using a long-acting anesthetic to impair natural respiratory defenses. We used this model to compare the efficacy of ceftazidime and tobramycin alone and in combination in the therapy of Pseudomonas pneumonia. The two antibiotics were shown to be synergistic in vitro for the strain of Pseudomonas aeruginosa tested. Treated animals receiving both antibiotics had fewer viable bacteria remaining in lung tissues (P less than 0.05) and exhibited a trend towards improved survival in comparison to animals receiving a single drug. In this model of Pseudomonas pneumonia, in vitro synergy was reflected by increased efficacy in vivo.

New cephalosporins cefotaxime, cefpimizole, BMY 28142, and HR 810 in experimental pneumococcal meningitis in rabbits.

Four new cephalosporins, cefotaxime, cefpimizole (U 63196E), BMY 28142, and HR 810 were evaluated in experimental pneumococcal meningitis. Cefotaxime penetrated only moderately into the cerebrospinal fluid of rabbits with meningitis, whereas cefpimizole, BMY 28142, and HR 810 all exhibited unusually good penetration. The bactericidal activity in infected cerebrospinal fluid was comparable for the four drugs.

Endocarditis due to methicillin-resistant Staphylococcus aureus in rabbits: expression of resistance to beta-lactam antibiotics in vivo and in vitro.

Whether a strain of methicillin-resistant Staphylococcus aureus susceptible to cephalothin by the disk-diffusion method was also susceptible to cephalothin in vivo was evaluated in the rabbit model of endocarditis. Rabbits with aortic-valve endocarditis due to methicillin-resistant S. aureus that were treated for four days with cephalothin had the same numbers of organisms in vegetations as did untreated rabbits. Treatment with cephalothin caused emergence of a highly resistant subpopulation in aortic-valve vegetations. Organisms highly resistant to cephalothin were also highly resistant to nafcillin. Thus broth-dilution and disk-diffusion tests may not predict therapeutic failure for cephalothin against strains of methicillin-resistant S. aureus. Because of cross-resistances among beta-lactam drugs, these strains should be considered uniformly resistant to this general class of antimicrobial agents, regardless of results from these tests.

Single versus combination antibiotic therapy for pneumonia due to Pseudomonas aeruginosa in neutropenic guinea pigs.

Studies of therapy for experimental pneumonia due to Pseudomonas aeruginosa have failed to document beta-lactam-aminoglycoside synergy for most antibiotics examined, in contrast to results usually observed with pseudomonas infections at other sites. The neutropenic guinea-pig model of pseudomonas pneumonia was modified to resemble more closely therapy for clinical infections. Animals were treated 16 hr after infection with ticarcillin, azlocillin, ceftazidime, tobramycin, and netilmicin, alone and in combination. As predicted by in vitro synergy testing, in all cases combination drug therapy was more effective than the corresponding drugs given alone (P less than .05), as assessed by quantitative lung culture. Among single-drug regimens, those in which peak antibiotic levels did not exceed the minimal bactericidal concentration for the organism were significantly less effective. Resistance to aminoglycosides did not develop during therapy, and therefore, in this study does not explain the mechanism of synergy observed with beta-lactam antibiotics.

Antibacterial activity of beta-lactam antibiotics in experimental meningitis due to Streptococcus pneumoniae.

In order to define the characteristics of the antibacterial activity of beta-lactam antibiotics in the treatment of bacterial meningitis, the relationship between cerebrospinal fluid (CSF) drug concentrations and the rate of bacterial killing was investigated for penicillin G and four new cephalosporins in an animal model of meningitis due to Streptococcus pneumoniae. All five drugs showed a significant correlation between increasing drug concentrations in CSF and increasing bactericidal rates. Minimal activity was observed in CSF at drug concentrations of approximately the broth minimal bactericidal concentration (MBC). Maximal activity occurred with CSF concentrations 10-30 times higher. In vitro tests did not reproduce the unique correlation of increasing drug concentrations and killing activity found in vivo. When evaluating new beta-lactam antibiotics for the treatment of bacterial meningitis, it is reasonable to establish a minimum standard of CSF drug concentrations of greater than or equal to 30 times the MBC against the infecting organism.

Interactions between folate and ascorbic acid in the guinea pig.

Possible interactions between folic acid (folate) and ascorbic acid (AA) have been suspected because megaloblastic anemia is occasionally observed in scorbutic patients, and it may or may not respond to folate treatment. Male weanling guinea pigs were fed diets containing high levels of folate and AA or diets deficient in one or both vitamins. A total of 36 animals, including 9 controls, were studied. When anorexia began to appear in the deficient groups, all animals were killed by exsanguination, and tissue samples (blood, liver, adrenal, kidney, spleen, and intestinal mucosa) were removed for AA and folate analyses. Folate and AA deficiency lowered tissue folate and AA levels, respectively. AA deficiency, either alone or in combination with folate restriction, did not affect tissue folate levels, nor did AA deficiency significantly exacerbate the anemia and leukopenia caused by folate deficiency. However, there was an unexpected decrease in AA levels in the liver and adrenal glands with folate deficiency. Although AA does not appear to be needed for normal folate metabolism, the lower AA levels associated with a folate deficiency are indicative of an interaction between the two vitamins.