A Quantitativ Study of the Alterations in the Fecal Flora of Man Following Oral Administration of Aureomycin
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Abstract
Conflicting reports have appeared concerning the ability of broad-spectrum antibiotics to reduce the population of the intestinal flora. The purpose of this investigation has been to study in detail the alterations in fecal flora following oral administration at aureomycin (chlortetracycline) with the hope of attaining a better understanding of the changes.
Nineteen normal young adults were each given either aureomycin or terramycin, 250 mg, orally 4 times daily for 5 days in a great majority of the cases. In bacteriological studies, fecal specimens were studied daily for a period of 5 days before medication, during the 5 days' course of medication and following the medication until the fecal flora had returned to pre-drug levels. A sample totaling one gram was taken from several portions of each fecal specimen, blended into a homogeneous suspension in 9.0 ml of sterile distilled water, and diluted serially in sterile distilled water. The total aerobes were enumerated in pour plates at B.B.L. eugonagar. The total anaerobes (including facultatives) were counted with B.B.L. anaerobic agar and Brewer anaerobic culture dishes. The coliforms were enumerated in pour plates of Difco Violet Red Bile Agar. The yeasts were counted on grape juice agar. The numbers of staphylococci were determined on Dileo Staphylococcus Medium and the organisms obtained were tentatively identified by Gram stain and Catalase test. Streptococcus faecalis was counted in DiFco S F Medium. The tubes of broth were incubated at 45.5 c. for 48 hours and the most probable number of Str. faecalis in each specimen was then determined from the tables of Prescott, Proteus and Pseudomonas, when present, were enumerated as Difco SS medium. All cultures were incubated aerobically at 37 C. for 48 hours, followed by 24 hours' incubation at room temperature. The coliforms were usually counted at the end of the first 24 hours' incubation. Total aerobes, total anaerobes and coliforms were not identified further. The yeasts were further studied in corn meal agar for the formation of pseudomycelia and chlamydospores. Representative strains of Staphylococcus aureus were studied for their ability to produce coagulase and to hemolyse blood. Strains of Proteus were identified culturally. In aerological studies, blood samples were taken before medication and at intervals following medication if Proteus was present. The sera in each case were treated for agglutination against one strain of the organism isolated from the same subject.
A definite alteration in the fecal flora was obaerved in all subjects. Aureomycin and terramycin behaved in a similar manner. In one case, 20 mg of aureomycin orally per day for 15 days produced no appreciable alteration in the fecal flora except for a 100-fold increase in yeasts. In another case, a high dosage (2.5 gram aureomycin orally per day for 8 1/2 days) produced no greater alteration than did the usual one gram per day. Generally the pattern of alterations in the fecal flora varied considerably from subject to subject and from organism to organism. The common pattern of alteration for each group of organisms studied are:
1. Coliforms: The pattern of alteration generally noted in 14 subjects was a decrease in numbers of coliforms quickly followed by an increase. The maximal decrease usually occurred on the second or third day following the start of the medication. The maximal increase in population following the initial decrease occurred in a period from 2 to 21 days following cessation of medication. The average was about 6 days. Another pattern of alternation was noted in 3 subjects in whom there was no appreciable change in coliform population throughout the course of study. In one subject, the medication resulted in complete disappearance of coliforms for stool cultures. For all the subjects studied, it required a period of from 0 to 15 days following cessation of the medication for the number of coliforms to return to their pre-drug levels.
2. Total aerobes and total anaerobes: Generally, these organisms seemed to follow the same patterns as did the coliforms, but their decreases in numbers during medication was often less marked and in no case were they eliminated completely. These groups of microorganisms returned to normal in from 0 to 17 days (average about 7 days) following cessation of medication.
3. Yeasts: Yeasta were found in 11 subjects. Only Candids albicans was isolated from 6 of the 11 subjects. The remaining 5 subjects had C. albicans and other identified yeasts. Nine of these 11 subjects showed a rapid 100-fold to 1000-fold increase without undergoing an initial decrease in yeast population during medication. A period of from 0 to more than 15 days after cessation of medication was required for the yeast counts to return to their pre-drug levels. In this group four subjects who did not have detectable yeast before medication showed the presence of and proliferation of yeasts during and following medication. The remaining 2 of the 11 subjects showed fluctuations but no significant increase in the yeasts population during and following the medication.
4. Staphylococci: Staphylococci were studied in 18 cases. Their responses to medication were, in general, less uniform than in the case of the other organisms studied. However, three major patterns of alternation were observed. In 3 subjects the decrease or disappearance of staphylococci due to medication was quickly followed by an increase in the population up to or above pre-drug levels. In another 3 subjects there were some fluctuations but no significant alterations in staphylococcal populations due to medication. A 100-fold to 1000-fold increase without any initial decrease in population due to medication was noted in the remaining 12 subjects. It took a period of from 2 to 15 days, or slightly longer, following cessation of medication for the number of staphylococci to return to their pre-drug levels for all subjects who had an increase in staphylococci. Five of these 18 subjects harbored hemolytic and coagulase-positive Staph. aureus and 2 other subjects harbored coagulase negative Staph. aureus.
5. Streptococcus faecalis: In 8 subjects there was increase of 100-fold to 10000-fold in population without an initial decrease during medication. Three subjects showed only insignificant fluctuations in the numbers of Str. faecalis throughout the course of study. In one subject Str. faecalis disappeared completely from his feces for a day or so shortly following medication. It took from 0 to 17 days for the numbers of Str. faecalis to return to their pre-drug levels following cessation of the medication.
6. Proteus: Proteus mirabilis was found in 10 of the 19 subjects studied. Nine subjects from whom Proteus could not be isolated before medication showed the presence of P. mirabilis on the second or third day of medication. In the remaining subject, a P. mirabilis carrier, this organism disappeared on the 4th day of medication, followed by a reappearance and a marked rise in numbers to above the initial pre-drug level. In almost all cases rapid proliferation of this organism to over 10^7 organisms per gram of wet feces was noticed within 4 days following the appearance or reappearance of the organism. There is no evidence that a marked rise in Proteus causes a dysentery-like diarrhea. It took a period of from 6 to 25 days following cessation of medication for the organism to disappear or to return to its initial pre-drug level.
7. Pseudomonas aeruginosa: The stools of only one subject showed the presence of Pseudomonas on the third day of medication. It increased in numbers to 10^6 organisms per gram of wet feces in 2 days, then began to decrease, and finally disappeared 5 days following cessation of medieation.
In this investigation with one exception the rapid proliferation of Proteus, staphylococci, yeasts, Str. faecalis, Pseudomonas and Other organisms did not cause any complications. One female subject developed urethritis due to P. mirabilis while her fecal Proteus were rapidly increasing in number toward the end of medication. This organism, identical with the Proteus in her feces, was repeatedly isolated and was the predominant organism in the urethral discharge and first portions of her urine specimens. The organism did not disappear from her urethral cultures until the 33rd post-drug day and 24 days following disappearance of Proteus from her feces.
In the serological studies, only 2 of the Proteus carrying subjects showed alight increases in agglutinen titers. One is the subjects who developed Proteus urethritis and the other subject did not experience any ill effect from the overgrowth of Proteus in his feces.
Generally speaking, the alterations of the fecal flora following oral aureomycin or terramycin as reported here are less marked than those reported by other investigators. Oral administration of these antibiotics by no means renders the intestinal tract sterile. The time limit for achieving a maximal effect from the medication is stressed. Factors contributing to differences in experimental results in regard to the effect of these antibiotics on the fecal flora are discussed. Also given is an extensive review of the literature concerning the alterations in intestinal flora of man and animals treated with commonly used antimicrobial agents.
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Thesis (Ph.D.)--Boston University
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