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Sulfonamide-Resistant Staphylococci: Correlation of in Vitro Sulfonamide—Resistance with Sulfonamide Therapy

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Sulfonamide-Resistant Staphylococci: Correlation of in Vitro Sulfonamide—Resistance with Sulfonamide Therapy SULFONAMIDE-RESISTANT STAPHYLOCOCCI: CORRELATION OF IN VITRO SULFONAMIDE—RESISTANCE WITH SULFONAMIDE THERAPY Wesley W. Spink, J. J. Vivino J Clin Invest. 1944;23(2):267-278. https://doi.org/10.1172/JCI101490. Research Article Find the latest version: https://jci.me/101490/pdf SULFONAMIDE-RESISTANT STAPHYLOCOCCI: CORRELATION OF IN VITRO SULFONAMIDE-RESISTANCE WITH SULFONAMIDE THERAPY1 By WESLEY W. SPINK AND J. J. VIVINO (From the Division of Internal Medicine, University of Minnesota Hospials and Medical School, Minneapolis) (Received for publication September 20, 1943) A feature of sulfonamide therapy for bacterial from patients and previous sulfonamide therapy infections is that species of bacteria differ in carried out in these patients? Is the develop- their resistance to the antibacterial action of the ment of strain resistance a permanent charac- compounds. It is also recognized that strains of teristic of the bacteria? microorganisms within the same species display Several species of bacteria have been rendered variations in susceptibility. A disconcerting resistant to the in vitro and in vivo action of the and confusing factor associated with chemo- sulfonamides. Many of the investigations have therapy, which appears to be assuming increasing been carried out with different strains of the clinical significance, is the ease and frequency pneumococcus (1 to 5). Sesler and Schmidt (6) with which some species of bacteria may develop observed the development of sulfonamide-re- in vtro and in vivo resistance to the bacteriostatic sistant pneumococci, and concluded that strains action of the sulfonamides. In the literature, the vary in developing this sulfonamide-resistance; term "sulfonamide-fast" has been applied to that a given strain develops resistance to the those strains which become resistant to the several sulfonamides at different rates; that the antibacterial action of the compounds. This is more susceptible a parent strain is to the action particularly applicable to studies involving of a sulfonamide, the more difficult it is to develop species of bacteria whose progenitors were known resistance; and that strains which become re- to be sensitive to the sulfonamides. Because the sistant to one sulfonamide, are resistant to all development of resistance is a relative phenome- the other compounds tested. There is evidence non, and because, under proper experimental that the development of sulfonamide-resistant conditions, the growth of even the most resistant pneumococci is more than a temporary phe- strains of bacteria may be inhibited by the drugs, nomenon (7 to 9). On the other hand, sulfona- the term "sulfonamide-resistant" is believed to mide-resistant pneumococci are sensitive to the be a more accurate description. action of specific antipneumococcus serum. The purpose of this report is to review briefly Hemolytic streptococci, particularly Lancefield the problem of sulfonamide-resistant bacteria in group A strains, are usually quite susceptible to general, and to record the results of investiga- the action of sulfanilamide, and yet strains in tions with several strains of staphylococcus this group may acquire in vitro and in vivo re- isolated from patients. An attempt has been sistance to the drug (10, 11). While staphy- made to answer the following questions: If a lococci as a species are more refractory to the standard in vitro test is used for quantitating bacteriostatic effect of all of the sulfonamides the inhibitory effect of the sulfonamides upon than are pneumococci and hemolytic streptococci, the growth of staphylococci, do strains of this it has been demonstrated that strains of staphy- species vary in their susceptibility to the anti- lococci may develop an increased resistance to staphylococcic action of the compounds? Is the compounds (12, 13). Gram-negative species there any correlation between the isolation of of bacteria, whose growth is usually inhibited sulfonamide-resistant strains of staphylococci in vitro by the sulfonamides, have been shown to develop sulfonamide-resistance. These in- IAided by grants from the Committee on Scientific Research, American Medical Association, and the Charles clude E. coli (14, 15), B. abortus (16), meningo- P. DeLaittre Research Fund, University of Minnesota cocci (17), and Shigella paradysentariae (strains Medical School. of Flexner and Sonne) (18). Strains of gono- 267 268 WESLEY W. SPINK AND J. J. VIVINO cocci, a species which is highly susceptible to the ant strains. The patients finally recovered, bacteriostatic action of the sulfonamides, have although a strain isolated from the blood of one been made resistant to sulfanilamide and sulfa- of the victims was still resistant to sulfanilamide. pyridine (19, 20). Carpenter and his associates It was observed by Cohn and his associates (31), (21) could not develop an increased tolerance of in gonorrheal patients who did not respond 10 strains of gonococci to sulfathiazole over a favorably to therapy with sulfathiazole, that period of 3 months. Nevertheless, this has been strains of gonococci from these individuals fre- accomplished by Kirby (22). quently showed in vitro evidence of resistance to If invasive strains of microorganisms develop sulfathiazole. Similar observations have been resistance to the sulfonamides both in vitro and recorded by Petro (32). Strains of staphylococci in experimental animals, the question immedi- have been shown to develop sulfonamide-resist- ately arises as to whether such a phenomenon ance in patients undergoing therapy with one of may transpire in human subjects while they are the sulfonamides (13). being treated with one of the sulfonamides, and As a species, the staphylococcus is generally whether the development of sulfonamide-re- more resistant to the sulfonamides than are sistant strains will affect the ultimate recovery several other species of pyogenic bacteria. of the patient. While caution must be exercised However, several experimental and clinical in transposing quantitatively in vitro data or the studies, carried out at the University of Minne- results of animal protection tests with the sul- sota Hospitals, have revealed that the sulfon- fonamides to the problem of chemotherapy in amides are effective antistaphylococcic agents human subjects, these data are often quite (13, 33 to 37). As a result of these investiga- helpful in directing the clinical application of the tions, sulfathiazole has been accepted at the drugs. Several investigators have confirmed University Hospitals as the most effective of the the observation that specific types of pneu- available sulfonamides in the therapy of staphy- mococci isolated from patients have shown an lococcic sepsis, but this still leaves much to be initial sensitivity to a sulfonamide, but as desired. While the failure of patients with chemotherapy proceeded, subsequent isolation of staphylococcic infections to respond to therapy the same type of pneumococcus revealed the with sulfathiazole is dependent upon several development of sulfonamide-resistance (8, 23 to factors, the apparent increasing incidence of 28). In some instances, coincident with the patients having infections due to staphylococci detection of sulfonamide-resistant pneumococci, which are highly resistant in vitro to sulfathiazole the patients' condition became worse or they merits further inquiry. failed to respond as anticipated. Similar ob- servations have been made with other species of MATERIALS AND METHODS OF STUDY bacteria. Francis (29) encountered a group of 13 individuals on a plastic surgery ward whose Investigations have been carried out with a total of 57 strains of staphylococci, obtained from an equal number of lesions were infected by a group A, type 12, patients who had various types of staphylococcic infec- strain of beta hemolytic streptococcus, and the tions. Isolation of the parent strains was made in brain local application of sulfanilamide was without broth or on veal agar-blood plates. The strains were then effect. In vitro tests showed the organisms to grown on slants of veal agar, having a pH of 7.8, and kept be resistant to sulfanilamide, although other in the refrigerator until ready for transfer to a synthetic strains of this type had been shown to be quite medium. Only those strains were selected for study which gave a positive coagulase test. This test provides the sensitive. It is of interest that the local appli- most simple procedure for identifying pathogenic strains cation of gramicidin in one case eradicated the of staphylococci (39). Sodium sulfathiazole was selected infection. Strains of Brucella abortus, sensitive for testing the resistance of the microorganisms. Com- to the in vitro action of sulfanilamide, have been parative observations with sulfanilamide, sodium sulfa- sulfathiazole made sulfanilamide-resistant by repeated ex- pyridine, sodium sulfadiazine, and sodium revealed that staphylococci were inhibited in their growth posure of the organism to the drug. Green (30) to a greater degree by sodium sulfathiazole than by the reported that 2 individuals in a laboratory other sulfonamides. Furthermore, strains that were became infected with these sulfanilamide-resist- resistant to sodium sulfathiazole were more resistant to the SULFONAMIDE-RESISTANT STAPHYLOCOCCI 269 aforementioned compounds. A water-clear medium of dl B phenylalanine 5.0 grams known chemical constituents, buffered to give a pH of 7.4, dl lysine.2 HCI 5.0 grams was employed in testing the staphylococci for their re- glycine 2.5 grams sistance
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