Kenneth C. Haltalin

Double-blind treatment study of shigellosis comparing ampicillin, sulfadiazine, and placebo

A double-blind treatment study comparing ampicillin, sulfadiazine, and placebo was performed in 52 infants and children hospitalized for shigellosis. Bacteriological failure rates in patients treated with placebo and sulfadiazine were 75 per cent and 39 per cent, respectively, compared with 6 per cent in ampicillin-treated patients. Clinical failure occurred in 56 per cent of patients treated with placebo, 39 per cent in sulfadiazine-treated patients and in none of the patients who received ampicillin. Ampicillin is a safe and highly effective drug for the treatment of shigellosis.

Comparative efficacy of nalidixic acid and ampicillin for severe shigellosis

Nalidixic acid is effective in vitro against shigellae including strains multiply-resistant to antibiotics. A comparative study of acute shigellosis in infants and children involved 19 patients treated with ampicillin and 17 treated with nalidixic acid. Stool cultures remained positive longer with nalidixic acid treatment than with ampicillin therapy, and clinical response was slower. The rate of response to therapy was correlated with the serum levels of ampicillin. Though nalidixic acid eliminates shigellae from stools more rapidly than with symptomatic therapy alone, it cannot be recommended for routine treatment of acute shigellosis since it has little effect on the natural course of the illness. In special circumstances when dealing with shigellae that are resistant to ampicillin, tetracycline, and chloramphenicol, nalidixic acid may have a limited use.

Absorption of ampicillin and nalidixic acid by infants and children with acute shigellosis.

Thirty‐seven infants and children with acute shigellosis were treated with orally administered ampicillin or nalidixic acid. Peak plasma levels and dose‐response curves suggested two patient populations. Five of 16 patients receiving nalidixic acid had a pronounced delay in absorption, while the others had the anticipated peak levels and plasma half‐lifes. All patients had a lower percentage of conjugated drug and of drug present as the hydroxynalidixic acid metabolite on the first day of treatment than during convalescence. Thus, some patients with diarrhea had altered absorption and all had altered metabolism of nalidixic acid during the acute phase of shigellosis. In 10 of 21 ampicillin‐treated patients there were depressed plasma levels and prolonged half‐lifes. These were statistically likely to be younger, to have more severe diarrhea, and to have lower body weight than those with normal peak plasma levels and plasma clearance rates.

Comparison of orally absorbable and nonabsorbable antibiotics in shigellosis. A double-blind study with ampi-cillin and neomycin.

The effects of orally administered neomycin and ampicillin on bacteriological cure and clinical course in acute shigellosis were assessed by a double-blind treatment study of 30 hospitalized infants and children. “Bacteeriological failure” (cultures positive more than 48 hours after initiation of therapy) occurred in 87 per cent of patients who received neomycin and in 13 per cent of those treated with ampicillin. All Shigellae showed in vitro susceptibility to the antibiotics used. “Clinical failure” (persistence of diarrhea beyond 5 days after starting therapy or removal of the patients from study or both) occurred in 60 per cent of the neomycin-treated group and in 13 per cent of those treated with ampicillin. Statistically significant differences between neomycin and ampicillin therapy were also demonstrated for the following parameteers: days until stool culture was negative, presence of Candida species in the stool, and days until afebrile. The failure of oral neomycin therapy in shigellosis supports the concept that nonabsorbable antimicrobial agents are not optimal therapy for acute shigellosis regardless of in vitro susceptibility.

Comparative Efficacy of Cephalexin and Ampicillin for Shigellosis and Other Types of Acute Diarrhea in Infants and Children

Most ampicillin-resistant Shigella are susceptible to cephalexin. Randomized treatment with cephalexin or ampicillin was given to 154 infants and children with acute diarrhea. Rectal swab cultures revealed Shigella in 42%, Salmonella in 6%, enteropathogenic Escherichia coli in 2%, and no pathogen in 50%. Cephalexin failed to eradicate Shigella after 5 days of treatment in 76% of patients as contrasted with 28% of ampicillin-treated patients with susceptible organisms. Shigella persisted in 78% of ampicillin-treated patients with resistant organisms. Diarrhea lasted more than 5 days in 43% of cephalexin-treated patients, in 56% of the ampicillin group with resistant organisms, but in only 9% of ampicillin-treated patients with susceptible organisms. The failure of cephalexin was due to the relatively high minimal inhibitory concentrations and minimal bacterial concentrations of 5 or 10 μg/ml and, although serum concentrations were twice the minimal bacterial concentration, they were not sufficient to demonstrate killing by the serum dilution method. In vitro susceptibility or resistance of Shigella to ampicillin correlated with clinical success or failure. Cephalexin is not a suitable drug for treatment of shigellosis in patients with ampicillin-resistant organisms.

In Vitro Susceptibility of Shigella Strains to Trimethoprim and Sulfamethoxazole

Trimethoprim and sulfamethoxazole were tested alone and in combination against 227 recently isolated Shigella strains. Variations in medium constituents and inoculum size were used to determine the optimal testing conditions. The plate dilution method with addition of 5% lysed horse blood to the susceptibility test medium and an inoculum size of 102 organisms was found to provide satisfactory results. All 227 strains were inhibited by low concentrations of trimethoprim, and all were susceptible to the combination of 0.06 μg of trimethoprim per ml and 1.25 μg of sulfamethoxazole per ml. Sixteen percent of these strains were resistant to ampicillin, 33% to tetracycline, 15% to chloramphenicol, and 27% to cephalothin. Based on these in vitro observations, trimethoprim and sulfamethoxazole appear worth evaluating for treatment of shigellosis due to multiply antibiotic-resistant strains.

Comparison of intramuscular and oral ampicillin therapy for shigellosis.

Twenty-four patients with severe shigellosis were treated with intramuscular ampicillin, 100 mg. per kilogram per day in 4 divided doses for 5 days. They were compared with patients previously treated orally with the same dosage of ampicillin. Clearing of Shigellae from the stools was significantly more rapid with the intramuscular route of administration. Alterations in enteric flora were different in the 2 groups. Patients treated orally were more likely to have the intestinal flora replaced with Candida species in contrast with those treated parenterally who were more apt to have overgrowth with species of Klebsiella-Aerobacter. Though each mode of ampicillin administration is effective in the treatment of shigellosis, the intramuscular route results in a more prompt eradication of Shigellae and is useful in the treatment of patients who are not able to take medication orally.

Optimal dosage of ampicillin for shigellosis

Thirty infants and children hospitalized for severe shigellosis received oral ampicillin,50 mg. per kilogram per day, for 5 days. Bacteriologic observations and clinical responses were compared with those in patients who had received 100 mg. per kilogram per day of the drug. There were no statistically significant differences between the two dosage groups with respect to bacteriologic cure rates and clinical responses. Super-infection with Candida species occurred less commonly in patients who received the lower dosage. Daily observations on persistence of fever, diarrhea, and positive stool cultures were compared in 103 hospitalized patients who received either of the two dosage schedules of oral ampicillin, intramuscular ampicillin, or placebo. All 3 modes of ampicillin therapy are effective in treatment of shigellosis when the infecting organism is susceptible. Parenteral administration is attended with a significantly more rapid bacteriologic response and lysis of fever and is therefore recommended for the severely ill patient. For others, although there is a tendency to slower response than with 100 mg. per kilogram per day, the lower oral dosage of ampicillin is satisfactory.

Comparison of orally absorbable andnonabsorbable antibiotics in shigellosis

The effects of orally administered neomycin and ampicillin on bacteriological cure and clinical course in acute shigellosis were assessed by a double-blind treatment study of 30 hospitalized infants and children. “Bacteeriological failure” (cultures positive more than 48 hours after initiation of therapy) occurred in 87 per cent of patients who received neomycin and in 13 per cent of those treated with ampicillin. All Shigellae showed in vitro susceptibility to the antibiotics used. “Clinical failure” (persistence of diarrhea beyond 5 days after starting therapy or removal of the patients from study or both) occurred in 60 per cent of the neomycin-treated group and in 13 per cent of those treated with ampicillin. Statistically significant differences between neomycin and ampicillin therapy were also demonstrated for the following parameteers: days until stool culture was negative, presence of Candida species in the stool, and days until afebrile. The failure of oral neomycin therapy in shigellosis supports the concept that nonabsorbable antimicrobial agents are not optimal therapy for acute shigellosis regardless of in vitro susceptibility.

IN-VITRO SUSCEPTIBILITY OF E. COLI, SHIGELLAE AND SALMONELLAE TO KANAMYCIN AND THERAPEUTIC IMPLICATIONS*

The scarcity of reports on kanamycin treatment of enteropathogenic Escherichia coli, Shigella and Salmonella infections is surprising in view of the almost uniform in-uitro susceptibility of these organisms to the drug. In part this may be due to the lack of a suitable commercial preparation for oral use in children and, in part, to a reluctance to desert the longer experience with other drugs that have proved generally satisfactory in these infections. The following observations are based on a review of the literature and on experience with a 6-year study of diarrheal disease in 937 hospitalized infants and children. Included are 274 patients (29 per cent) with enteropathogenic E . coli diarrheal disease, 143 patients (15 per cent) with shigellosis and 37 patients (4 per cent) with salmonellosis. Additional Shigella strains were obtained from cases of acute bacillary dysentery in our outpatient department, from an institution for retarded children, and from Houston and New Orleans.