cefamandole and Disease-Models--Animal

Quinupristin-dalfopristin (Q-D) is an injectable streptogramin active against most gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). In experimental endocarditis, however, Q-D was less efficacious against MRSA isolates constitutively resistant to macrolide-lincosamide-streptogram B (C-MLS(B)) than against MLS(B)-susceptible isolates. To circumvent this problem, we used the checkerboard method to screen drug combinations that would increase the efficacy of Q-D against such bacteria. beta-Lactams consistently exhibited additive or synergistic activity with Q-D. Glycopeptides, quinolones, and aminoglycosides were indifferent. No drugs were antagonistic. The positive Q-D-beta-lactam interaction was independent of MLS(B) or beta-lactam resistance. Moreover, addition of Q-D at one-fourth the MIC to flucloxacillin-containing plates decreased the flucloxacillin MIC for MRSA from 500 to 1,000 mg/liter to 30 to 60 mg/liter. Yet, Q-D-beta-lactam combinations were not synergistic in bactericidal tests. Rats with aortic vegetations were infected with two C-MLS(B)-resistant MRSA isolates (isolates AW7 and P8) and were treated for 3 or 5 days with drug dosages simulating the following treatments in humans: (i) Q-D at 7 mg/kg two times a day (b.i.d.) (a relatively low dosage purposely used to help detect positive drug interactions), (ii) cefamandole at constant levels in serum of 30 mg/liter, (iii) cefepime at 2 g b.i.d., (iv) Q-D combined with either cefamandole or cefepime. Any of the drugs used alone resulted in treatment failure. In contrast, Q-D plus either cefamandole or cefepime significantly decreased valve infection compared to the levels of infection for both untreated controls and those that received monotherapy (P < 0.05). Importantly, Q-D prevented the growth of highly beta-lactam-resistant MRSA in vivo. The mechanism of this beneficial drug interaction is unknown. However, Q-D-beta-lactam combinations might be useful for the treatment of complicated infections caused by multiple organisms, including MRSA.

Topics: Animals; Anti-Bacterial Agents; Cefamandole; Cefepime; Cephalosporins; Disease Models, Animal; Drug Resistance, Microbial; Drug Resistance, Multiple; Drug Therapy, Combination; Endocarditis, Bacterial; Humans; Lincosamides; Macrolides; Microbial Sensitivity Tests; Rats; Staphylococcal Infections; Staphylococcus aureus; Time Factors; Virginiamycin

The relationship between the degree of chronic middle ear inflammation and pneumatization was investigated in the pig as an animal model, since its tympanic bulla closely resembles the human mastoid air cell system. Ten piglets (sire: Landrace-Hampshire crossbreed; dam: Duroc) were used for this experiment. Four ears of two animals served as the normal control group and 16 ears of eight animals were the experimental group. In this latter group, otitis media was induced by injecting glycerin into the middle ear clefts 1 months after birth, and the degree of inflammation was varied by administering or withholding antibiotics (cefamandole and dibekacin) and adjusting the dosage regimen. The animals were sacrificed 6 months after birth and examined for the relationship between the degree of chronic middle ear inflammation present and tympanic bulla pneumatization. Various degrees of inflammation were successfully induced by injecting the antibiotics: the more severe the inflammation found, the greater was the inhibition of pneumatization. Findings demonstrated that the degree of inhibition of pneumatization produced was directly proportional to the severity of chronic middle ear inflammation.

Topics: Animals; Bone Resorption; Cefamandole; Chronic Disease; Dibekacin; Disease Models, Animal; Ear, Middle; Epithelium; Glycerol; Image Processing, Computer-Assisted; Injections, Intramuscular; Osteoblasts; Osteoclasts; Osteosclerosis; Otitis Media; Swine; Temporal Bone

LY 146032, teicoplanin, vancomycin, oxacillin, cephalothin, cefamandole, ampicillin plus sulbactam, and cefoperazone plus sulbactam were studied against six isolates of staphylococci (including both Staphylococcus aureus and coagulase negative staphylococci) using in vivo and in vitro methods. In vitro susceptibility measurements demonstrated that all six isolates were sensitive to LY 146032 and vancomycin and that five of six isolates were sensitive to tiecoplanin, cefamandole, ampicillin plus sulbactam, and cefoperazone plus sulbactam. Comparison of antimicrobial therapy in an in vivo rabbit model demonstrated that cefoperazone plus sulbactam was active against the greatest number of isolates (five of six) based on a reduction of greater than or equal to 5.0 log10 colony forming units per milliliter (CFU/ml) from growth control at the end of the animal treatment study. Vancomycin and oxacillin were equal in achieving reductions of greater than or equal to 5.0 log10 CFU/ml in four of the six isolates. Comparing each isolate's in vivo outcome to in vitro data shows that in vitro susceptibility tests overpredict the sensitivity of these six isolates to LY 146032 and vancomycin, are variable for teicoplanin, cefamandole, ampicillin plus sulbactam, and cefoperazone plus sulbactam, and underpredict for oxacillin.

Topics: Ampicillin; Animals; Anti-Bacterial Agents; Cefamandole; Cefoperazone; Cephalothin; Daptomycin; Disease Models, Animal; Female; Glycopeptides; Oxacillin; Peptides; Rabbits; Staphylococcal Infections; Sulbactam; Teicoplanin; Vancomycin

The in vitro activity of four cephalosporins was compared with their effects in an experimental thigh infection (cefuroxime and cefamandole against Escherichia coli and cefamandole, ceftriaxone, and ceftazidime against Klebsiella pneumoniae) in granulocytopenic mice. The effect in vitro (ER) was defined as the difference between the growth rate without antibiotic and the growth rate at the steepest part of a 3-h growth curve in the presence of an antibiotic. The relation between concentration and ER was described with the Hill equation. Using pharmacokinetic parameters of the plasma concentrations in vivo and those of the Hill equation the corresponding time course of ER was calculated and by integration with respect to time (0tERdt), an estimate was obtained of the effect on bacteria. For all four antibiotics this estimate was significantly correlated with the actual values of the effect in vivo (EN), defined as the difference in numbers of bacteria between controls and antibiotic-treated animals at 4 h.

Topics: Agranulocytosis; Animals; Cefamandole; Ceftazidime; Ceftriaxone; Cefuroxime; Cephalosporins; Disease Models, Animal; Escherichia coli; Escherichia coli Infections; Klebsiella Infections; Klebsiella pneumoniae; Mice; Protein Binding; Specific Pathogen-Free Organisms

Cefamandole, cefoxitin, cefotetan, ceftizoxime, imipenem plus cilastatin, and ampicillin plus sulbactam were compared in the eradication of subcutaneous abscess in mice caused by Bacteroides fragilis group organisms and Escherichia coli alone or in combination. The abscesses were examined 5 d after inoculation. B. fragilis group reached log10.1-11.0 organisms per abscess and E. coli log11.6-12.5. Imipenem plus cilastatin significantly reduced (in 6.9-10.6 logs) the number of E. coli and all members of B. fragilis group alone or in all combinations. Ampicillin plus sulbactam reduced the numbers of all B. fragilis group (in 4.2-7.2 logs) but was less effective against E. coli (reduction of 1.8-4.2 logs). Cefoxitin was effective in significantly reducing (in 4.9-6.2 logs) the number of E. coli and all members of B. fragilis group alone or in all combinations. Cefotetan was effective against B. fragilis (reduction of 5.1-6.6 logs) and E. coli alone or in combination but did not reduce the number of Bacteroides thetaiotaomicron, Bacteroides vulgatus, and Bacteroides ovatus. Ceftizoxime was effective against only B. ovatus (reduction of 3.7-5.8) and E. coli (reduction of 6.0-8.1 logs); it did not reduce the number of other organisms. Cefamandole was effective against only E. coli and was not effective against any member of the B. fragilis group. These in vivo data confirm the in vitro activity of these antimicrobials.

Topics: Abscess; Ampicillin; Animals; Anti-Bacterial Agents; Bacteroides fragilis; Bacteroides Infections; Cefamandole; Cefotetan; Cefoxitin; Ceftizoxime; Cilastatin; Cilastatin, Imipenem Drug Combination; Disease Models, Animal; Drug Combinations; Drug Therapy, Combination; Escherichia coli; Escherichia coli Infections; Imipenem; Male; Mice; Skin Diseases; Sulbactam

Hemorrhagic shock has been associated with an increased risk of infection after injury. The immediate and long term effects of hemorrhagic shock without tissue injury on the susceptibility of an animal to infection and the efficacy of antibiotic prophylaxis to prevent infection in this setting were examined. Sprague-Dawley rats were subjected to hemorrhagic shock (LD15) by bleeding to a mean arterial pressure of 45 millimeters of mercury for 45 minutes and were resuscitated with shed blood and normal saline solution. In one experiment, dorsal wounds were inoculated one hour before or after shock with either 10(6), 10(8) or 10(10) Staphylococcus aureus. In a second experiment, rats were infected at one hour, or one, three or five days after shock with 10(6), 10(7) or 10(8) S. aureus. Equivalent numbers of rats received cefamandole nafate prior to bacterial challenge. Hemorrhagic shock increased the susceptibility to wound infection at all inocula. Infection increased whether rats were wounded before or after shock, and this effect was sustained for up to three days. Antibiotic prophylaxis was of limited value in reducing the incidence of wound infection after shock.

Topics: Animals; Cefamandole; Disease Models, Animal; Disease Susceptibility; Female; Rats; Rats, Inbred Strains; Shock, Hemorrhagic; Staphylococcal Infections; Time Factors; Wound Infection

Cephalosporin antibiotics cause a variety of hematologic disturbances in man, the pathogeneses and hematopathology of which remain poorly characterized. There is a need for a well-defined animal model in which these blood dyscrasias can be studied. In four subacute toxicity studies, the intravenous administration of cefonicid or cefazedone to beagle dogs caused a dose-dependent incidence of anemia, neutropenia, and thrombocytopenia after 1-3 months of treatment. A nonregenerative anemia was the most compromising of the cytopenias and occurred in approximately 50% of dogs receiving 400-500 mg/kg cefonicid or 540-840 mg/kg cefazedone. All three cytopenias were completely reversible following cessation of treatment; the time required for recovery of the erythron (approximately 1 month) was considerably longer than that of the granulocytes and platelets (hours to a few days). Upon rechallenge with either cephalosporin, the hematologic syndrome was reproduced in most dogs tested; cefonicid (but not cefazedone)-treated dogs showed a substantially reduced induction period (15 +/- 5 days) compared to that of the first exposure to the drug (61 +/- 24 days). This observation, along with the rapid rate of decline in red cell mass parameters of affected dogs, suggests that a hemolytic component complicated the red cell production problem and that multiple toxicologic mechanisms contributed to the cytopenia. We conclude that the administration of high doses of cefonicid or cefazedone to dogs can induce hematotoxicity similar to the cephalosporin-induced blood dyscrasias described in man and thus provides a useful model for studying the mechanisms of these disorders.

Topics: Anemia; Animals; Cefamandole; Cefazolin; Cefonicid; Cephalosporins; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Female; Hematologic Diseases; Male; Neutropenia; Thrombocytopenia

Cephalosporin treatment in man has been associated with blood dyscrasias that include a time- and dose-related anemia, neutropenia, and thrombocytopenia, the hematopathology of which remains poorly characterized. A similar hematologic syndrome can be produced in dogs following daily intravenous injections of 540-840 mg/kg cefazedone or 400-500 mg/kg cefonicid for 1-3 months. Using this animal model, histologic and cytologic changes in blood, bone marrow, spleen, and liver were studied over the course of the cephalosporin-induced cytopenias. Peripheral blood cytologic observations included an absence, generally, of erythroid regenerative changes, increased numbers of macroplatelets, spherocytosis, erythroblastemia, and toxic neutrophil morphology. Interim and postmortem cytologic and histologic observations of bone marrow included hypoplastic and toxic changes, primarily in cytopenic dogs receiving high doses of cefonicid, and regenerative changes in hematopoietic tissue of affected cefazedone-treated animals. The latter included variable erythroid hyperplasia, increased megakaryocytes, and decreased marrow fat and was accompanied by evidence of extra-medullary hematopoiesis and increased hemosiderin and hemophagocytosis in liver and splenic tissue. The incidence and severity of these changes were dose-dependent, corresponded with the cytopenias observed peripherally, and, like the cytopenias, were fully reversible. These observations suggest that the hematologic syndrome associated with cephalosporin treatment in the dog has multiple toxicologic mechanisms, which include peripheral cytotoxic effects and bone marrow damage with depressed or ineffective hematopoiesis.

Topics: Animals; Bone Marrow; Cefamandole; Cefazolin; Cefonicid; Cephalosporins; Disease Models, Animal; Dogs; Hematopoiesis; Liver; Neutrophils; Paraproteinemias

Topics: Animals; Cefamandole; Cefonicid; Cephalosporins; Disease Models, Animal; Leukocyte Count; Mice; Surgical Wound Infection