Fortified antibiotic ointment in bacterial keratitis.

We conducted experiments to determine the effectiveness of fortified antibiotic ointment in the treatment of Pseudomonas keratitis in rabbits. We evaluated gentamicin ointment (3, 10, 20, and 40 mg/g), gentamicin solution (3 and 10 mg/ml), and placebo, each given every 30 minutes. We also examined the effectiveness of fortified ointment given in extended treatment intervals. In short-term trials, commercial-strength gentamicin solution (3 mg/ml) was therapeutically superior (P less than .001) to commercial-strength gentamicin ointment (3 mg/g) in reducing corneal bacterial colony counts. No significant difference in antimicrobial effect was noted between fortified gentamicin ointment and fortified gentamicin solution at 30-minute treatment intervals. Fortified gentamicin ointment reduced colony counts even at extended treatment intervals of up to four hours in a severe keratitis model.

Hemolytic uremic syndrome associated with Corynebacterium diphtheria infection.

Although hemolytic uremic syndrome (HUS) is usually idiopathic, it follows a number of infections. The pathogenesis of post-infectious HUS is endothelial cell damage by either circulating endotoxin or exotoxin. Diphtheria exotoxin has never been implicated in HUS. We report HUS following diphtheria infection in a 9 yr old un-immunized white female admitted with a short history of sorethroat and thrombocytopenia. There were hemorrhages in sclera, gums and left tonsillar area and a grayish exudate on right tonsil. Laboratory values revealed Hgb 14.4 g/dl, decreasing to 7.6 g/dl, WBC/26,900 mm3, platelet count 7,000/mm3. Bone marrow examination revealed normal megakaryocytes. She was oliguric with BUN 214 mg/dl, serum creatinine 12.4 mg/dl and serum uric acid 19.2 mg/dl. Despite peritoneal dialysis, red cell and platelet transfusions and exchange transfusion she expired. A postmortem examination was refused. A throat culture done on admission grew corynebacterium species which was later confirmed to be toxigenic C. diphtheriae. Diphtheria exotoxin inactivates an enzyme in cytoplasm which is necessary for peptide chain elongation. This may have interfered with prostacyclin synthesis thereby allowing the development of HUS.

Recurrent seizures after diphtheria, tetanus, and pertussis vaccine immunization. Onset less than 24 hours after vaccination.

Twenty-two patients with recurrent seizures that started less than 24 hours after immunization with diphtheria, tetanus, and pertussis (DTP) vaccine were retrospectively studied. The initial seizure generally occurred after one of the first three DTP vaccine immunizations, and followed that immunization by less than 12 hours. Two of the 22 patients were siblings. Eight patients had additional immunizations with DTP vaccine and four had immediate worsening of their seizures. Of the 22 patients, only one was seizure free and stopped taking anticonvulsants. Three patients exhibited normal development, and 11 had severe developmental delays. Based on these observations, we reviewed current contraindications for immunization with pertussis vaccine.

Experimental Pseudomonas aeruginosa sepsis: absence of synergy between ticarcillin and tobramycin.

An in vivo model of Pseudomonas aeruginosa sepsis was developed with normal and neutropenic guinea pigs injected intravenously with a strain of Pseudomonas demonstrated in vitro to be synergistically susceptible to ticarcillin and tobramycin. Therapy with ticarcillin, tobramycin, or a combination of the two starting 4 hr after intravenous injection of microorganisms was administered every 2 hr for periods up to 40 hr. Each therapy was associated with significant reductions in bacterial counts in blood, liver, spleen, and kidney compared with untreated animals. In no tissue in either normal or granulocytopenic animals did therapy with a combination of ticarcillin and tobramycin reduce bacterial counts significantly more effectively than did the better single antibiotic agent alone. These findings suggest that when ticarcillin and tobramycin are administered to animals at doses equivalent to therapeutic doses given in humans, a synergistic effect in reduction of bacterial counts in parenchymal organs and blood is not observed. These studies may help explain clinical reports in humans describing a lack of synergistic activity of combination antibiotic therapy in patients with Pseudomonas sepsis.

Factors that influence the efficacy of topical gentamicin prophylaxis for experimental Pseudomonas keratitis.

We evaluated the efficacy of topical gentamicin prophylaxis for experimental Pseudomonas keratitis in rabbits by applying gentamicin in concentrations of 0.3 and 4 mg/100 ml, in both solution and ointment vehicles, one or four hours after a superficial stromal scratch was infected topically with Pseudomonas organisms. Under these conditions the most effective prophylaxis was that given early, in solution, and in high concentration.

Experimental bacterial keratitis: a quantitative model of leukocyte migration following transfusion.

A model for the study of polymorphonuclear leukocyte (PMN) migration after transfusion employing induction of keratitis in guinea pigs was developed. Initial studies demonstrated that compared with other agents, intracorneal injection of Pseudomonas aeruginosa following in vivo labelling of PMN by administration of 3H-thymidine produced the greatest influx of radiolabelled PMN into corneas. In subsequent studies, donor peritoneal PMN were radio-labelled by injection of donors with 3H-thymidine. Neutropenia was induced in recipients by whole body irradiation, and they were infected intracorneally with Pseudomonas prior to transfusion. Corneal radioactivity was assayed 24 h after induction of keratitis and the number of donor PMN in corneas was calculated. Half-life of transfused PMN in non-neutropenic recipients was 1.9 h. Arrival of labelled PMN at infected corneas in recipient animals ranged between 0.1-1.0% of transfused cells. Exposure of donor PMN to sonication or to 45 degrees C for 20 min reduced the proportion of PMN arriving at infected corneas (P less than 0.001). Storage of PMN for 24 h at 4 degrees C led to a greater ingress of donor PMN compared with storage at 37 degrees C (P less than 0.01). This model allows quantitation of in vivo PMN function after transfusion and should allow assessment of the effects of most aspects of PMN transfusion technique upon such function.

Determination of posttransfusion granulocyte kinetics by chemiluminescence in chronic granulomatous disease.

A 14 year old boy with CGD of childhood received HLA-matched granulocyte transfusions in the therapy of an intramural abscess of the ileum. Donor granulocyte survival after transfusion was determined with the endotoxin-stimulated NBT test as well as an assay of chemiluminescence employing whole blood. The presence of circulating donor PMNs after transfusion was documented by both techniques. The half-life of donor cells in the first 5 hr following transfusion was approximately 1.4 hr with both techniques. The greatest number of transfused cells was detected by both methods in the patient's blood immediately after the completion of the transfusion. At this time 22.7% of the expected increment in donor PMN concentration was detected by the NBT test, and 13.8% of the expected increment was detected by chemiluminescence assay. Both techniques allow studies of posttransfusion granulocyte kinetics in CGD because of the basic underlying metabolic abnormality of recipient but not donor cells. The chemiluminescence assay may also be adaptable to use in neutropenic patients receiving PMN transfusions.

Relative efficacy of the topical use of amikacin, gentamicin and tobramycin in experimental Pseudomonas keratitis.

In a quantitative model of experimental Pseudomonas aeruginosa keratitis in guinea pigs, topical solutions of amikacin, gentamicin and tobramycin were equally effective. Solutions of 20 mg/ml were more effective than solutions of 3 mg/ml.

Experimental Pseudomonas keratitis in guinea-pigs: therapy of moderately severe infections.

We have previously shown that antibiotic therapy of experimental Pseudomonas keratitis was more effective in early moderate infections than in late severe infections. The purpose of this study was to determine the relative efficacies of various drugs, routes, and vehicles in the treatment of moderately severe infection. As in the late severe infections, the most consistently effective regimen was an aminoglycoside applied topically in solution. No synergistic or additive effect was observed with a combination of aminoglycoside given topically and a penicillin given intramuscularly. Topical therapy with antibiotic in ointment was less effective than topical therapy with antibiotic in solution.

Comparison of therapeutic routes in experimental Pseudomonas keratitis.

We determined the efficacy of tobramycin administered by topical, intramuscular, and subconjunctival routes in guinea pigs and rabbits with experimental Pseudomonas keratitis. The topical route of administration was consistently more effective than either subconjunctival or intramuscular routes. Subconjunctival injection of antibiotic did not enhance the effectiveness of topical therapy in either guinea pigs or rabbits. Intramuscular tobramycin was more effective than saline in guinea pigs with keratitis but not in rabbits with keratitis.

Cryotherapy for experimental Pseudomonas keratitis.

The effectiveness of cryotherapy alone and in combination with topical tobramycin sulfate therapy for experimental Pseudomonas keratitis was determined in guinea pigs and rabbits. Results were evaluated quantitatively by determining numbers of viable bacteria surviving in corneas. A brass probe cooled to--79 degrees C and applied directly to infected corneas for six seconds resulted in an immediate 99.9% reduction in bacteria. One freeze-thaw cycle followed by topical tobramycin therapy was significantly more effective than tobramycin therapy alone in five of six strains tested. None of the corneas treated with tobramycin alone demonstrated no growth, whereas 24 of 42 of these infected corneas showed no growth after the combination treatment. We conclude that cryotherapy alone had a rapid bactericdal effect on experimental Pseudomonas keratitis and that it significantly potentiated topical antibiotic therapy for most strains.

Staphylococcal keratitis. Experimental model in guinea pigs.

An experimental model of staphylococcal keratitis in guinea pigs was devised that is suitable for quantitative evaluation of therapy. The growth curve in the cornea of a virulent strain of Staphylococcus aureus was determined. The organism multiplied rapidly, reached a peak in about 12 hours, and began to decline in numbers after three days. Infections were relatively resistant to therapy begun 24 hours after infection was established. Treatment started earlier when fewer bacteria were present was more effective than treatment begun later. Treatment begun at the time of infection, which might be considered prophylaxis, was highly effective. When treatment was begun eight hours after infection, tobramycin sulfate and gentamicin sulfate solutions administered topically in doses of 20 mg/ml were more effective than topical bacitracin, erythromycin, clindamycin phosphate, or a solution containing polymyxin B sulfate, neomycin sulfate, and gramicidin. Bacitracin and erythromycin ointments were ineffective.

Therapeutic effect of topical antibiotic on untreated eye in experimental keratitis.

We studied the systemic absorption ot topical tobramycin and amikacin in experimental Pseudomonas keratitis in guinea pigs. After giving two drops of tobramycin 40 mg/ml every 30 minutes for 24 hours to both infected eyes (the corneal epithelium having removed) the mean serum concentration was 1.5 mcg/ml. Treatment of one of the infected eyes with the same strength of tobramycin or amikacin drops did not alter the number of viable bacteria in contralateral eyes treated with saline. Tobramycin 400 mg/ml or amikacin 250 mg/ml however, decreased the number of viable bacteria in the contralateral eyes. We conclude that the therapeutic effect on the contralateral eye was the result of systemic absorption.

Bacteriologic cure of experimental Pseudomonas keratitis.

Two long-term therapy trials with high concentrations of antibiotic were carried out to determine the duration of therapy required to achieve bacteriologic cure of experimental Pseudomonas keratitis in guinea pigs. In the first study, corneas still contained Pseudomonas after 4 days of continual topical therapy with either tobramycin 400 mg/ml, amikacin 250 mg/ml, ticarcillin 400 mg/ml, or carbenicillin 400 mg/ml. In an 11-day trial of topical therapy with tobramycin 20 mg/ml, 34 of 36 corneas grew no Pseudomonas after 6 or more days of therapy. The bacteriologic response to therapy in this model occurred in two phases. About 99.9% or more of the organisms in the cornea were killed in the first 24 hr of therapy. The numbers of bacteria remaining in the cornea declined gradually over the next several days until the corneas were sterile. Optimal antibiotic therapy may include two stages: initial intensive therapy with high concentrations of antibiotic applied frequently to achieve a large rapid decrease in numbers of organisms in the cornea, followed by prolonged, less intensive therapy to eradicate organisms and prevent relapse.

Topical tobramycin therapy of experimental Pseudomonas keratitis: an evaluation of some factors that potentially enhance efficacy.

We evaluated several therapeutic modifications in an attempt to improve efficacy of topical therapy with tobramycin of experimental Pseudomonas keratitis in guinea pigs. Removal of corneal epithelium enhanced efficacy of topical therapy with 0.3 mg/ml and 3 mg/ml tobramycin sulfate but did not influence therapy with 40 mg/ml or 400 mg/ml tobramycin. The highest concentration of antibiotic was the most effective; 7 of 12 infected corneas treated with 400 mg/ml tobramycin were sterile in 48 hours. Therapy begun soon after the infection was established, when there were relatively few organisms present, was more effective than therapy begun later, when there were many more bacteria in the cornea. Our results are consistent with a basic therapeutic concept. The most effective regimen is one that achieves the highest safe concentration of antibiotic at the site of infection as early in the course of infection as possible.

Corticosteroid in experimentally induced Pseudomonas keratitis: failure of prednisolone to impair the efficacy of tobramycin and carbenicillin therapy.

The effect of prednisolone on tobramycin and carbenicillin therapy for experimentally induced Pseudomonas keratitis was evaluated. Results were assessed quantitatively by determining the number of bacteria that survived in the cornea. Simultaneous administration of prednisolone did not adversely alter results of treatment with carbenicillin or tobramycin. In another trial, pretreatment with prednisolone for 48 hours before antibiotic therapy was begun did not change significantly the results of therapy with intramuscular tobramycin or carbenicillin. We conclude that corticosteroid therapy does not affect adversely results of antibiotic therapy with tobramycin or carbenicillin in this experimental model.

Antibiotic therapy of experimental Pseudomonas keratitis in guinea pigs.

Antibiotic therapy of experimental Pseudomonas keratitis was evaluated quantitatively by determining numbers of viable bacteria in the cornea of guinea pigs. Topically applied carbenicillin disodium, gentamicin sulfate, and tobramycin sulfate were often significantly more effective than topically applied polymyxin B sulfate. Intramuscular therapy with tobramycin was as effective as topical therapy, and the results exhibited less variability. Topical tobramycin every 30 minutes was significantly more effective than topical therapy every 60 minutes. No combination of antibiotics was significantly better than a single effective drug. The concentration of tobramycin in the aqueous correlated more closely to therapeutic efficacy than did the concentration in the cornea. Although all antibiotics reduced numbers of bacteria in the cornea by more than 99% in the first 24 hours of therapy, none was able to sterilize the cornea in four additional days of continuous therapy. Persistence of organisms despite apparently adequate topical therapy may explain some reported cases of relapse in humans.