Actinomyces pyogenes: susceptibility of 103 clinical animal isolates to 22 antimicrobial agents V Guérin-Faublée, Jp Flandrois, E Broye, F Tupin, Y Richard

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V Guérin-Faublée, Jp Flandrois, E Broye, F Tupin, Y Richard. Actinomyces pyogenes: susceptibility of 103 clinical animal isolates to 22 antimicrobial agents. Veterinary Research, BioMed Central, 1993, 24 (3), pp.251-259. ￿hal-00902121￿

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Actinomyces pyogenes: susceptibility of 103 clinical animal isolates to 22 antimicrobial agents

V Guérin-Faublée JP Flandrois E Broye F Tupin Y Richard

1 Laboratoire de Microbiologie et Immunologie, École Nationale Vétérinaire de Lyon, 1, avenue Bourgelat, BP 83, 69280 Marcy-l’Étoile; 2 Unité de Recherche Associée au CNRS 243, Laboratoire de Bactériologie Hôtel-Dieu de Lyon, 1 Place de I Hôpital, 69002 Lyon, France

(Received 22 June 1992; accepted 15 September 1992)

Summary ― Actinomyces pyogenes induces suppurative diseases in ruminants and many other animal species. Most of the earlier antimicrobial susceptibility data has been obtained by disk diffu- sion techniques. Minimal inhibitory concentrations (MIC) of 22 for 103 strains of A pyo- genes of animal origin were determined by agar dilution test (Mueller-Hinton agar supplemented with 5% sheep blood). All the strains were susceptible to penicillin G, amoxicillin, methicillin, cephal- othin, cefoperazone, pristinamycin, kanamycin, , , , van- comycin, novobiocin and rifampin. Fifty-nine percent were resistant to , 67% to tetracy- cline, and , 12% to , and . Most of the strains resistant to and exhibited a constitutive MLS(B)-like phenotype. In the cultural conditions used, it was not possible to determine accurate MIC of fucidic acid and peflox- acin.

Actinomyces pyogenes I antibiotics I minimal inhibitory concentrations (MIC)

Résumé ― Actinomyces pyogenes : sensibilité de 103 souches d’origine animale à 22 anti- biotiques. Les concentrations minimales inhibitrices (CMI) de 22 antibiotiques pour 103 souches dActinomyces pyogenes d’origine animale ont été déterminées par la technique de dilution en milieu solide (gélose Mueiler-Hinton + 5% de sang de mouton). Toutes les souches étaient sensibles à la pénicilline G, I amoxicilline, la méticilline, la céfalotine, la céfopérazone, la pristinamycine, la kana- mycine, la gentamicine, la spectinomycine, le chloramphénicol, la vancomycine, la novobiocine et la rifampicine. Cinquante neuf pour cent étaient résistantes à la streptomycine, 67°/ à la tétracycline, la doxycycline et la minocycline, 12% à l’érythromycine, la spiramycine et la lincomycine. La plupart * Correspondence and reprints des souches résistantes aux macrolides et lincosamides avaient un phénotype semblable au phéno- type MLS (8) constitutif. Il n a pas été possible de mesurer précisément les CMI d’acide fusidique et de péfloxacine dans les conditions de culture utilisées.

Actinomyces pyogenes lantibiotiques / concentrations minimales inhibitrices / (CMI)

INTRODUCTION growing bacteria (Rhoades, 1979). A pyo- genes is moderately susceptible to cipro- The species Actinomyces pyogenes (for- floxacin, enrofloxacin, and chloramphenicol merly Corynebacterium pyogenes) was (Hjerpe and Routen, 1976; Burrows, 1980; Pre- proposed by Reddy et al (1982) on the ba- Mitani et al, 1980; Gedek et al, 1984; sis of its morphological, physiological and scott and Yielding, 1990). For this latter biochemical characteristics. The transfer drug, only a few resistant strains have been Rhoades and Natter- was further confirmed by Collins and described by (1979) Jones (1982). mann and Horsch (1976) whose studies in- cluded a number of 30% of This pathogen is commonly isolated large isolates; resistant strains have been reported by from pyogenic processes in cattle, sheep, goats and pigs, and its distribution in these Hjerpe and Routen (1976). species seems worldwide. It is occasional- A pyogenes is slightly more susceptible ly found in other species. It seems to thrive to than the other Actino- best in closed or partly closed cavities and myces species. However, according to causes bronchopneumonia, endometritis, many studies, most of the strains have ac- abortions, abscesses, generalized infec- quired resistance to streptomycin (Hjerpe tions, arthritis and summer mastitis in cat- and Routen, 1976; Rhoades, 1979; Bur- tle. A pyogenes has been isolated in many rows, 1980; Mitani et al, 1980; Gedek et al, cases from clinically normal animals and it 1984, 1988; Buchholz, 1985). Results from is therefore believed that it is an opportu- Nattermann and Horsch (1976), and Kunt- nistic pathogen. There are a few records of er (1975) are contradictory; this could be infections in humans (Kotrajaras et al, due either to the origin (milk versus respir- 1982; Kotrajaras and Togami, 1987). atory tract) of their isolates or to the date of The in vitro susceptibility of A pyogenes the study. Resistance to kanamycin or to antimicrobial compounds is variable. Ear- is unusual (Hjerpe and Routen, lier studies have indicated that all isolates 1976; Rhoades, 1979), and exceptional in are resistant to nalidixic acid, norfloxacin, the case of gentamicin (Burrows, 1980; and colistin (Mitani et al, 1980; Prescott and Gedek et al, 1988). The activity of specti- Yielding, 1990). According to Rhoades nomycin must be confirmed (Bulling, 1954; (1979), about one-fourth of the strains are Kunter, 1975; Nattermann and Horsch, susceptible to polymyxin B when using the 1976; Hjerpe and Routen, 1976; Rhoades, disk diffusion method but the few minimal 1979; Gedek et al, 1984; Buchholz, 1985). inhibitory concentrations (MIC) recorded are The percentages of strains resistant to the about 128 mg/l (Hjerpe and Routen, 1976; representatives of the family Buchholz, 1985). Most of the strains have vary between different authors (0% to an intermediate level of susceptibility to nov- 80%) (Bulling, 1954; Kunter, 1975; Hjerpe obiocin (Hjerpe and Routen, 1976) but ap- and Routen, 1976; Nattermann and pear susceptible when using disk diffusion Horsch, 1976; Rhoades, 1979; Gedek et test and zone diameter standards for fast- al, 1984; Buchholz, 1985). A pyogenes is highly susceptible to all and the pristinamycin components I and II from the fi-lactam antibiotics: penicillins A and Rh6ne-Poulenc (Vitry, France); pefloxacin from Bellon sur are the most effective mole- Roger Laboratory (Neuilly Seine, cefoperazone from Pfizer France Co cules of this followed France); cefoperazone family, by cephalo- (Orsay, France); novobiocin from Upjohn Labor- thin and oxacillin; MIC reported for penicil- atory (Crawley, UK); lincomycin and spectinomy- lin G range from 0.015 to 0.1 mg/l (Bulling, cin from Upjohn Laboratory (La Defense, 1954; Hjerpe and Routen, 1976; Burrows, France); fucidic acid from Leo Pharmaceutical 1980; Mitani et al, 1980; Gedek et al, Products (Vernouillet, France); gentamicin, ka- 1984, 1988; Buchholz, 1985). A few strains namycin, streptomycin, erythromycin, chloram- and from resistant to G or have phenicol, tetracycline Vdtoquinol (Lure, penicillin ampicillin and from been France); cephalothin, vancomycin Lilly described by Rhoades (1979) and France (Saint Cloud, France); doxycycline from Nattermann and Horsch (1976). Rh6ne-M6rieux (Toulouse, France); amoxicillin Macrolides and lincosamides exhibit a from SmithKline Beecham Laboratory (Paris, from Lederle high inhibitory activity. Results show a ten- France); minocycline Laboratory (Oullins, rifampin from La- towards an resistance to France); Ciba-Geigy dency increasing boratory (Rueil-Malmaison, France). Methicillin macrolides and related antibiotics ranging (ref M-1757) was purchased from Sigma Chemi- from 20-80% of the strains without an evi- cal Co (St Louis, USA). dent explanation for these dissimilarities Rifampin, fucidic acid, chloramphenicol, spi- (Hjerpe and Routen, 1976; Rhoades, ramycin, erythromycin, pristinamycin, and the 1979; Burrows, 1980; Gedek et al, 1984, pristinamycin components I and II were first dis- 1988). A pyogenes is also susceptible to solved in a small amount of ethanol; tetracy- bacitracin and nitrofurantoin (Rhoades, cline, and lincomycin in methanol. The volume was then with distilled water to the final 1979; Mitani et al, and to trimetho- adjusted 1980) concentration. Further dilutions were made in and the sulfonamides when a suitable prim distilled water. The other drugs were dissolved medium is used to determine the MIC (Bar- and diluted in distilled water. nett and Bushby, 1970). The limited available MIC data for A pyogenes prompt us to reevaluate the in Bacterial strains vitro activity of various classes of antibio- tics recent clinical isolates of A against A set of 103 strains of A pyogenes was used in pyogenes. Apart from families this study. Ninety-three strains were collected by used in food animal practice, we included JL Martel (Laboratoire de Pathologie Bovine, antibiotics of other families essentially from CNEVA, Lyon, France) from clinical isolates and cases submitted to the Labora- an epidemiological point of view. Sulfona- post-mortem toires V6t6rinaires in France mides and were not tested Départementaux, trimethoprim between 1984-1990. The other strains were col- since a was observed for only poor growth lected by B Poutrel (INRA, Nouzilly, France), E A pyogenes on lysed horse blood agar. Richard (Laboratoire V6t6rinaire Ddpartemental, Lyon, France), J Vidal (Laboratoire V6t6rinaire Ddpartemental, Rodez, France) and V Gu6rin- MATERIALS AND METHODS Faubi6e (Laboratoire de Microbiologie et Immu- nologie, ENVL, Lyon, France). Ninety-seven strains were recovered from Antimicrobial agents cattle, 4 from sheep and 2 from goats; most of them (52 strains) were isolated from the respira- tory tract; 20, 6 and 4, respectively, from milk, The antimicrobial compounds tested as labora- foetuses and uterine discharges; 11 from vari- tory standard powder were kindly supplied as ous suppurative infections; 10 were of unknown follows: penicillin G, spiramycin, pristinamycin, origin. Organism identification was based on colony zu MPS 2000 spectrophotometer (Shimadzu, morphology, haemolysis, Gram staining and Kyoto, Japan). A dilution of the exponential classical biochemical characteristics (Krech and growth culture was made in sterile solution in Hollis, 1991). After biotyping, they were stored distilled water with sodium chloride 8 g/I (w/v) at -70 °C in brain-heart infusion broth supple- according to absorbance such that the final inoc- mented with 10% glycerol. ulum concentration was approximately 10! CFU/ ml. Quality controls were run using Staphylococ- cus aureus ATCC25923 and Escherichia coli ATCC25922. All the strains were grown aerobi- cally. MIC determination

The agar dilution method was used to determine Media and supplements the MIC of 22 drugs. Inocula were delivered by a Steers replicator apparatus (Denley Multipoint Inoculator A 400, Nattslane, A pyogenes strains were grown on trypto-casein Billingshurst, UK) for a final concentration of 104 soya agar (ref 64554, Diagnostics Pasteur, approximately CFU h Marnes-la-Coquefte, France) supplemented with per spot. After 18-20 of incubation at 37 °C under 5% sheep blood (ref 5 582 2, Bio M6rieux, Mar- atmospheric conditions, the MIC for each strain was recorded as the lowest concen- cy I’!toile, France). Liquid media used were tration of antibiotic no as brain-heart infusion broth (ref 0037-01-6, Difco, yielding growth deter- mined Detroit, USA) supplemented with 5% sterile by the naked eye; 1 to 3 colonies or a visible haze were not taken into account. horse serum (ref 295 990, Boehringer- barely Mannheim, Mannheim, FRG) and 0.1% (v/v) MIC interpretative standards of the Comite Tween 80 (ref 822 187, Merck, Darmstadt, de I’Antibiogramme de la Societe Frangaise de FRG). Microbiologie (Acar et al, 1991) were followed. Agar plates for MIC determination were pre- pared by adding 2 ml of antibiotic solution and 1 ml of sheep blood to 17 ml of melted Mueller- RESULTS Hinton agar (ref 64 884, Diagnostics Pasteur). All plates were stored at + 4 °C and used within The MIC of the 22 24 h. Growth was clearly visible after 24 h of (in mg/1) tested antimi- aerobic incubation in these conditions on control crobial agents for the 103 strains of A pyo- plates. genes are shown in table I and the MIC for the control strains in table II. In our experimental conditions, MIC of Inoculum preparation doxycycline, minocycline, pristinamycin component I and pefloxacin for quality con- Three to 5 colonies from Trypticase soy blood trol strains were 3-fold higher than those agar plate were suspended in brain-heart expected. MIC of the component II of pristi- infusion broth supplemented with 0.1% Tween namycin and of fucidic acid for S aureus 80 and incubated aerobically for 2 d at 37 °C. ATCC25923 were 16 and 16-32 re- Exponential growing inoculum was prepared by mg/l inoculating 30 111 of this first liquid medium spectively, although the reported MIC for culture into 10 ml of brain-heart infusion broth susceptible strains of this species are re- supplemented with 0.1 % Tween 80 and 5% ster- spectively 0.5 and 0.06 mg/l. For these 6 ile horse serum. The addition of 0.1% Tween antibiotics the absolute value of the MIC 80 to the liquid media during the growth of the cannot be taken into consideration but the organism prevented the formation of clumps and comparison within the A set of was necessary to obtain a reproducible inocu- pyogenes strains remains of value. lum with most of the strains of A pyogenes. After an overnight incubation at 37 °C, optical All strains were susceptible to f3-lactam density was measured at 430 nm on a Shimad- antibiotics (penicillin G, amoxicillin, methi- cillin, cephalothin, and cefoperazone), to The 61 (59%) resistant strains included pristinamycin, to chloramphenicol, to rifam- many different populations and 25 (24%) pin, to vancomycin, to novobiocin (2-16, strains had a high level of resistance. limits the and to given by manufacturer) Most of the strains (69 strains, 67%) aminoglycosides (gentamicin, kanamycin, were resistant to the tetracycline. For and spectinomycin) except streptomycin. these strains, MIC of doxycycline and mi- A bimodal response was observed to nocycline were very much higher than MIC streptomycin, the tetracycline family, mac- for strains susceptible to tetracycline. The rolides and lincosamides. resistance to the tetracycline family was Of the 103 strains studied, only 42 frequently associated with resistance to (41%) were susceptible to streptomycin. streptomycin (x2 = 4.6, P < 0.05). was phenotypically very similar to the con- stitutive MLS (B) resistance. Three strains were resistant to macrolides and lincosa- mides, but probably susceptible to pristi- namycin components I and II; they may be designated as ML-resistant strains.

DISCUSSION

All the strains of A pyogenes are naturally susceptible to numerous antibiotics with narrow or broad spectrum: f3-lactam antibi- otics, pristinamycin, gentamicin, kanamy- cin, chloramphenicol, rifampin, vancomycin and novobiocin. Only few strains are sus- ceptible to streptomycin and the i, tetracy- cline family but the majority remains sus- ceptible to macrolides and lincosamides. It was not possible to determine accu- rately the MIC of fucidic acid, doxycycline, minocycline, pristinamycin componentsI and II, and pefloxacin as MIC for the con- trol strains were higher than expected. The adjunction of blood to Mueller-Hinton agar, required for the correct growth of A pyo- genes may explain these problems. Inhibi- tion of fucidic acid by serum is recognised (Barber and Waterworth, 1962) as well as the adverse effect of traces of hemolysis on pristinamycin component II (Videau, for the are The patterns of resistance of A pyo- 1982). MIC tetracycline family genes to macrolides, lincosamides, and increased by an excess of Ca and Mg ions and In the cases on the basis of MIC tests (Brenner Sherris, 1972). are shown in table 111. A limited number of of pristinamycin component I and pefloxa- the be due to the strains (12 strains, 12%) showed a cross- cin, discrepancies may resistance between erythromycin, spiramy- increased growth rate of the control strains in the conditions. A suitable cin and lincomycin; all these strains were experimental medium for A susceptible to pristinamycin. Their suscep- pyogenes susceptibility test- tibility to pristinamycin component II was of ing to these antibiotics and to sulfona- mides and is under the same order of magnitude as that of trimethoprim investiga- - and lincosamide-susceptible tion. strains. Most of these strains (9/12) were MIC interpretative standards are defined resistant to pristinamycin component I as for fast growing bacteria; moreover, these their MIC were 2 to 4-fold superior to MIC values are based only on pharmacokinetic of the susceptible strains. This resistance studies in humans and the cut-off criteria does not necessary apply to bacteria path- bacteria: bacteria in exponential growth ogenic for animal species. are more susceptible to B-lactam antibio- In general, our results were in agree- tics than those in steady-state growth. MIC ment with those of Bulling (1954), Hjerpe of cephalothin were of the same order of and Routen (1976), Burrows (1980), Mitani magnitude as those reported for other Acti- et al (1980), Gedek et al (1984, 1988), and nomyces species (Lerner, 1974; Schaal et Buchholz (1985). Divergences in terms of al, 1979) but the species A pyogenes is es- effectiveness could be noted. Gedek et al pecially susceptible to penicillin G and pen- (1988) found higher MIC of spiramycin and icillins A (Lerner, 1974; Niederau et al, lincomycin for susceptible strains and 1982). According to our results, amino- Hjerpe and Routen (1976) in the case of sides except streptomycin exhibit a moder- novobiocin. A pyogenes seems to be more ate inhibitory activity against A pyogenes susceptible to lincosamides and novobio- but better than that described by Hjerpe cin than the other Actinomyces species and Routen (1976), Burrows (1980), and (Lerner, 1974; Niederau et al, 1982). In the Mitani et al (1980). Despite extreme varia- same way, we observed lower MIC of peni- tions in assay technique, the pattern of cillin G and cephalothin than the majority MIC of aminoglycosides was very different of authors (Hjerpe and Routen, 1976; Bur- to that of other Actinomyces species which rows, 1980; Mitani et al, 1980); this could are resistant to these compounds (Lerner, be due to the physiological state of the 1974; Schaal, 1986). MIC of minocycline, doxycycline, rifampin, and vancomycin were pyogenes suggests that these drugs the same as those of diverse Actinomyces should be useful in the management of an- species (Lerner, 1974; Schaal, 1986). imals with A pyogenes infections. Penicil- lins A to be an excellent alterna- A pyogenes was the only species of the appear tive. Some animals failed to to genus Actinomyces to harbour resistance respond if we exclude the limited resistance to ri- therapy without development of resistant fampin developed by A eriksonii and A strains. Whether or not MIC are attained naeslundii (Lerner, 1974). Sixty-seven and within a purulent environment could not be ascertained from the available literature. 59% of the strains were respectively resist- ant to the tetracycline family and to strepto- Moreover, A pyogenes is practically never the in lesions. mycin. These high frequencies were simi- only pathogen present lar to those previously reported by Hjerpe Regular MIC reports by a few laborato- and Routen (1976), Gedek et al (1984), ries seem to be sufficient to guide the vete- and Buchholz (1985), but differed from rinary surgeon. The use of an abbreviated those of Nattermann and Horsch (1976), form of the dilution procedure with only 2 and Kunter (1975) whose strains were col- concentrations of the antibiotics (the break- lected earlier. Resistant strains to macro- point concentrations) is under investiga- lides and related antibiotics were not as tion. numerous (about 10%), much fewer than reported by Hjerpe and Routen (1976), and Gedek et al (1984). Most of the strains ACKNOWLEDGMENT resistant to macrolides and lincosamides exhibited a resistance pattern that was We thank B Tilly for technical assistance. phenotypically very similar to the constitu- tive MLS(B) resistance in staphylococci the MIC of (Courvalin et al, 1985) although REFERENCES pristinamycin component I were not as high as those expected in such resistant strains. 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