Epidemiological and Genetical Study of Drug Resistance in Staphylococcus aureus

Abstract

Surveys of staphylococcal strains, isolated from clinical sources in geographically scattered hospitals in Japan, disclosed the following facts: 1) Triple (TC·SM·SA, TC·PC· SA, PC·SM·SA) and quadruple (TC·SM·PC·SA) resistant strains with reference to TC, SM, PC and SA, were manifest and they were restricted to specific phage group. 2) There is a maximum population of resistant strains (M.P.R.) in a restricted area, which is governed by the amount and period of use of a drug and by genetic characters of the bacteria such as the mutation rate to resistance, and character which governs infectivity and ability for successful parasitism. 3) There are two types of resistant strains: the first becomes resistant easily and consequently multiple resistant when a new drug is introduced, and consists largely of strains in phage group I containing phage type 80/81. The second type remains single (SA) or double (PC·SA; SM·SA) resistant, and consists primarily of strains in group II and III From the facts that all of the tested staphylococcal strains from clinical sources carry prophages and their drug resistance can be transduced to other strains by their prophages, the present author presents the hypothesis that transduction of drug resistance by prophage is mainly responsible for the acquisition of multiple resistance and wide distribution of multiple resistant strains in phage type or phage group.Genetic studies of drug resistance in staphylococci have disclosed the following facts: 1) Resistance to TC is easily transduced at high frequencies by prophages obtained from multiple resistant strains, and in various combinations of donors and recipients. Resistance to SA and SM is jointly transduced with TC, and vice donors and recipients. Resistance to SA and SM is jointly transduced with TC, and vice versa. Resistance to PC, the ability to form penicillinase (PCase), and chloramphenicol (CM) resistance is not transduced jointly with resistance to TC, SM, and SA. 2) Resistance to macrolide (Mac) antibiotics (EM, OM, LM, SP) is eliminated jointly and irreversibly by acriflavine treatment or by ultraviolet irradiation, and is transduced jointly by phages obtained from donor strains. From these results it can be concluded that Mac resistance is located on an extrachromosomal plasmid. 3) Because of the genetic character of PCase formation (PCase+) and irreversible elimination of PCase+, it was concluded that the gene which governs PCase formation is located on a plasmid. And there are two types of plasmid; one which carries the genetic characters of resistance to macrolide antibiotics (Macr) and of the penicillinase formation (PCase+) and the other carries only PCase+. A genetic model for the genes which govern resistance to TC, SM, SA and for the plasmids is presented. 4) The genetic character which governs resistance to CM is irreversibly eliminated during storage of stock culture or by treatment with acriflavine. This fact and results from transductional analysis suggest that the gene responsible for CM resistance may be located on a plasmid, probably different from the plasmids which govern (Macr. PCase+) or (PCase+). The findings that CM resistant strains of S. aureus inactivated CM in the presence of acetylcoenzyme A strongly suggest that CM resistance in strains from clinical sources is accounted for by inactivation of CM through acetylation of the drug molecule.

Transduction Analysis of the Genetic Determinants for Chloramphenicol Resistance in Staphylococci

“…By contrast, it was demonstrated that the loci governing resistance to TC, SA and SM exist closely on a single genetic element according to the results of the joint transduction of (TC.SM) [14] and (TC.SA.SM)-resistance [8], which strongly suggests that this is probably on the cell's own chromosome. According to the epidemiological and genetic analysis of drug-resistance in staphylococci, the present authors feel that transduction of drug resistance and lysogenization by phages are responsible for the rapid acquisition of drug-resistance, wide distribution of multiply resistant staphylococci and for the shift to restricted phage-typing patterns [15,16]. The findings of joint transduction of drug-resistance exhibited as an additional support for this theory [8,13,14].…”

Decrease in Accumulation of Macrolide Antibiotics as a Mechanism of Resistance in Staphylococcus aureus

“…Bourse and Monnier [3] described some characteristics of the dissociated type of Mac-resistant strains. Mitsuhashi et al [5,7,11,18] have classified those Mac-resistant strains into 3 groups: i.e., (i) group A, strains which exhibited constitutive resistance to EM, OM, leucomycin (LM), spiramycin (SPM), and sometimes to lincomycin; (ii) group B, including strains resistant to EM and OM, whose resistance is induced by either EM or OM; and (iii) group C whose strains exhibited an inducible resistance in the presence of subinhibitory concentrations of EM. We have investigated the biochemical and physiological mechanisms of those types of Macresistance, and have reported on a decrease in accumulation of EM in cells of these resistant strains of S. aureus in a previous paper [12].…”

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“…Studies carried out in several laboratories have shown that, unlike other types of bacterial resistance, TC resistance is not due to either the modification of ribosome(s) and of protein synthetic machinery or of enzymatic destruction of the drug (3,8,10). Instead, the TC resistance in naturally occurring resistant strains of gram-positive and gram-negative bacteria is known to be due to a decrease in the permeability of the drug in bacterial cells resulting in the reduction of intracellular concentration of the drug (1-4).…”