The activity of roxithromycin was determined by a microdilution method, in comparison with erythromycin, spiramycin and josamycin. Roxithromycin and erythromycin showed very similar MICs against staphylococci, Streptococcus pneumoniae, Str. pyogenes and Haemophilia influenzae. In most cases, spiramycin and josamycin appeared similarly or more active. The activity of roxithromycin against Mycoplasma pneumoniae, Legionella spp., Chlamydia psittaci and, to some extent, against Pasteurella spp. was also assessed, by suitable in-vitro methods. Roxithromycin has a promising potential for treating selected skin and respiratory infection

Auckenthaler, R.

Pechère, J.-C

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Journal of Antimicrobial Chemotherapy (1987) 20, Suppl. B, 1-5In-vitro activity of roxithromycin againstrespiratory and skin pathogensJ.-C. Pecbere and R. AockenthakrDipartement de Microbiologie, CMU, 9, Avenue de Champel, 1211 Geneve 4,SwitzerlandThe activity of roxithromycin was determined by a microdilution method, incomparison with erythromycin, spiramycin and josamycin. Roxithromycin anderythromycin showed very similar MICs against staphylococci, Streptococcuspneumoniae, Str. pyogenes and Haemophilus influenzae. In most cases, spiramycinand josamycin appeared similarly or more active. The activity of roxithromycinagainst Mycoplasma pneumoniae, Legionella spp., Chlamydia psittaci and, to someextent, against Pastewella spp. was also assessed, by suitable in-vitro methods.Roxithromycin has a promising potential for treating selected skin and respiratoryinfections.IntroductionErythromycin is a macrolide antibiotic which is useful for therapy of respiratory andskin infections caused by susceptible micro-organisms such as Staphylococcus,Streptococcus, Mycoplasma, Chlamydia and Legionella spp. Roxithromycin is a newethero oxime derivative of erythromycin (Jones, Barry & Thomsberry, 1983) withimproved pharmacokinetic properties. This report compares the in-vitro activity ofroxithromycin, erythromycin, josamycin, and spiramycin against different micro-organisms causing skin or respiratory infections.Materials and methodsPersonal studiesA total of 247 bacterial isolates were collected by the Laboratoire Central deBacteriologie or, occasionally, in other Swiss hospitals. These isolates included 56Staph. aureus, 26 Staph. epidermidis, 24 Staph. saprophyticus, 62 Str. pneumoniae, 38Str. pyogenes, 20 Haemophilus influenzae and 21 Nocardia asteroides. The abovebacteria were typical strains, according to conventional identification methods. Theywere kept frozen in skim milk at — 70°C. Before study, organisms were thawed,streaked on to sheep blood agar and incubated overnight at 35°C. Standard antibioticpowders were obtained from their respective manufacturers. Antibiotic workingsolutions were prepared according to the instructions of the manufacturer and usedimmediately after appropriate dilution in water or in broth.Antimicrobial activity was measured in most cases by a microdilution method inMueller-Hinton broth, following the M7-T procedure specified by the National10305-7453/87/20B001 +05 $02.00/0 © 1987 The British Society for Antimicrobial Chemotherapy2 J--C. Pecbfee and R. AuckentnalerCommittee for Clinical Laboratory Standards (1983). The final inoculum of105-106 cfu/ml was prepared from a trypticase soy broth inoculated 4 h before andcontrolled by viable counts. The inoculum for H. influenzae was prepared and tested inBrain Heart Infusion broth supplemented with 5% nicotinamide diphosphate and 10%haemin. For all strains, except N. asteroides, the MIC was read after 18 h ofincubation at 35°C. N. asteroides was tested by agar dilution on Mueller-Hinton agarwith 10* cfu/spot with 35°C incubation for three days. In all cases, the MIC wasdefined as the lowest antibiotic concentration yielding no growth visible to the nalcedeye.Other studiesFor completion of this study, and after permission from their respective authors, somereports prepared for Roussel Uclaf, Paris, are quoted here. These reports and theirmethods follow. C. Bebear (Hopital Pellegrin Bordeaux, France) studied ten strains ofM. pneumoniae, and determined the MIC of macrolides in agar dilution (Hayflickmedium, pH 7-2, containing 20% of foal serum). K. Suzaki and Y. Niitu (TheResearch Institute for Tuberculosis and Cancer, Tohoku University, Japan) tested thegrowth inhibitory effect of roxithromycin on M. pnevmoniae by a microdilutionmethod using a standard mycoplasma broth (pH 7-6) without penicillin but withphenol red. J. Fleurette determined the MIC of roxithromycin for 98 strains ofLegionella spp. (30 reference strains from the CDC, Atlanta, Georgia, U.S.A.,representative of 15 different species and various serotypes; 34 strains of clinical origin;34 strains from the environment). This study was carried out by using the antibioticmedium No. 1 (Oxoid), supplemented with iron pyrophosphate (0-25 g/1) and L-cysteinhydrochloride (0-4 g/1). Three other reports, respectively by I. D. Farrell (Public HealthLaboratory service, East Birmingham Hospital, England), A. Bure (Hopital ClaudeBernard, Paris, France) and J. Acar (Hopital Saint Joseph, Paris, France) also dealtwith Legionella spp., but used BCYE medium (broth or agar). J. Orfila (C.H.U.,Amiens, France) studied growth inhibition of C. psittaci by macrolides andtetracyclines in a cell line (HELA 229). R. C. Spencer, Royal Hallamshire Hospital,Sheffield, England, determined the activity of roxithromycin against 10 strains ofPasteurella spp. isolated from skin infections.Results and discussionStaph. aureusThe collection of Staph. aureus was divided into three categories according to theactivity of benzyl-penicillin and oxacillin (Table I). Roxithromycin appeared active(MIC100 2 mg/1) against the strains that were susceptible to these two /Mactamcompounds, confirming previous studies (Jones, Barry & Thornsberry, 1983; Rolston,Le Blanc & Ho, 1986). Roxithromycin was also active against all strains that wereresistant to benzylpenicillin (MIC > 32 mg/1) and susceptible to oxacillin. Generally, inthis collection, the activity of roxithromycin was comparable with that of erythromycinwithin one dilution, with the exception of three strains for which the MIC oferythromycin was four to eight times higher than that of roxithromycin. Spiramycinand josamycin appeared to be slightly more active than erythromycin andRoxHhromydn: respiratory and skin pathogensTable 1. Activity of macrolides against skin and respiratory pathogens (personal data)Organisms(number)Penicillin-sensitiveStaph. aureus (IS)Penicillin-resistantoxacillin-sensitiveStaph. aureus {\9)Oxacillin-resistantStaph. aureus (20)Staph. epidermidis (26)Staph. saprophytiau (24)Str. pneumoniae (62)Str. pyogenes (38)H. influenzae (20)N. asteroides (21)AntibioticroxithromycinerythromycinspiramycinjosamycinroxithromycinerythromycinspiramycinjosamycinroxithromycinerythromycinspiramycinjosamycinroxithromycinerythromycinspiramycinjosamycinroxithromycinerythromycinspiramycinjosamycinroxithromycinerythromycinspiramycinjosamycinroxithromycinerythromycinspiramycinjosamycinroxithromycinerythromycinspiramycinjosamycinroxithromycinMIC50(mg/1)120-50-252410-2512812810-50-510-250-250-510-250-50-40-80-2010-250-2500601258888128MIC,0(mg/1)24112410-51281281281281281280-250-2532160-520-41-60-80-20-250-500601258888128Range(mg/1)0-5-21-160-25-10-25-0-51-22-40-5-10-25-0-5l - > 1282 - > 1280-5- > 1280-25- > 1280-25-128006-128006-1280125-1280-25-320-5-640-125-10-25-20-025-12-80-1-6-40012-3-20-025-0-40-06-0-250-125-0-5006-006006-01251-81-82-82-160-25- > 128roxithromycin. The phenotype of resistance was strikingly different when we dealtwith the oxacillin resistant strains (MIC > 32 mg/1). Eighteen of the 20 oxacillinresistant strains were also resistant to erythromycin and roxithromycin. The generaltrend towards higher macrolide MICs among the oxacillin-resistant Staph. aureus is aknown fact (Lyon & Skurray, 1987), already observed with roxithromycin (Joneset al., 1983; Rolston et al., 1986). As an exception, two oxacillin resistantStaph. aureus were susceptible to the four macrolides tested. Besides, ten of 20oxacillin resistant Staph. aureus demonstrated a so called dissociated phenotype ofresistance, according to the terminology initially proposed by Garrod (1957): they wereresistant to erythromycin, but sensitive to spiramycin and josamycin. Strains exhibitingthe dissociated phenotype are now known to be inducibly resistant to all the MLSB(Macrolides, Lincosamides, Streptogramin type B) group of antibiotics via amethylation mediated by small multicopy plasmids (Weisblum, 1985). Our study showsthat roxithromycin behaves as erythromycin and not as the two other macrolides inthis respect.4 J.-C. Pech&e and R. AockenthalerCoagulase-negative staphylococciAmong the 26 strains of Staph. epidermidis tested, 19 were susceptible (MIC < 2 mg/1)to the four macrolides tested, five expressed the dissociated phenotype, and twoexhibited generalized (Garrod, 1957) resistance. On a weight basis, activity oferythromycin and roxithromycin were comparable within one dilution, whilespiramycin and josamycin were two to eight times more potent. As reported by Joneset al. (1983), no significant differences were found in the MICs for the Staph.epidermidis, whether or not they produced penicillinase. As to Staph. saprophyticus, 20of 24 strains were susceptible to the four macrolides, whereas four strains showed adissociated phenotype of resistance.StreptococciAmong the streptococci, Str. pneumoniae and Str. pyogenes are the most frequentlyinvolved in respiratory and skin infections. Sixty-one of 62 strains of Str. pneumoniaeappeared to be sensitive to achievable concentrations of the four macrolides, but onestrain made an exception, exhibiting a quite resistant pattern. Here, the MICs wererespectively 12-8 mg/1 for roxithromycin, 6-4 mg/1 for erythromycin, 3-2 mg/1 forspiramycin and 0-4 mg/1 for josamycin. All 38 strains of Str. pyogenes appeared to besusceptible to the four macrolides, with similar activities of the compounds on a weightbasis. In the report by R. C. Spencer however, one erythromycin-resistant Str.pyogenes was also resistant to roxithromycin, and similar observations are reported inthe literature (Jones et al., 1983; Barlam & Neu, 1984).H. influenzaeRoxithromycin and the three other macrolides showed consistent, although modest,antimicrobial activity against type b (14 strains) and non-type b (6 strains)H. influenzae. The results reported in this study regarding the specific activity ofroxithromycin against H. influenzae are similar to the findings of Jones et al. (1983)and Jorgensen, Redding & Howell (1986), but slightly less favourable than thosereported by Barlam & Neu (1984) or by Chantot, Bryskier & Gasc (1986).Other bacteriaC. Bebear, dealing with ten strains of M. pneumoniae, reports that MICs were< 0-01 mg/1 for both erythromycin and roxithromycin in all cases. The report byK. Suzaki and Y. Niitu revealed that the strains resistant to erythromycin had asimilar degree of resistance to roxithromycin.According to J. Fleurette's report, the MIC100 of different species of Legionella wereas follows: 0-25 mg/1 for roxithromycin, 0-5 mg/1 for erythromycin and 1 mg/1 forjosamycin. This favourable activity was also reported by J. F. Acar, A. Bure andI. D. Farrell. Using her model of cell culture against C. psittaci, J. Orfila showed thatroxithromycin had an activity (inhibition of bacterial growth) starting at aconcentration of 0-5 mg/1. This activity was shown after 24 h of contact, increasingafter 48 h and 72 h, and was comparable with that of erythromycin, josamycin,tetracycline and minocycline. R. C. Spencer showed that the MICJ0 and MIC90 ofRoxithroraydn: respiratory and skin pathogens 5erythromycin and roxithromycin against Pasteurella spp. were 4 mg/1 for both drugs(range of MICs, 0-5-4 mg/1).In conclusion, macrolides such as erythromycin have a good activity againststaphylococci, streptococci, some Haemophilus strains, Legionella spp. and C. psittaciand have been extremely useful in diseases caused by these organisms. They have beenrecommended for upper respiratory infections, such as otitis, sinusitis, or eradicationof group A streptococci from the throat. Erythromycin is the standard therapy forM. pneumoniae and legionella pulmonary infection. Also, macrolides are indicated inmild respiratory or skin infections caused by streptococci or staphylococci, as analternative to /Mactams in penicillin-allergic patients.Roxithromycin, which shows antibacterial activity very similar to that oferythromycin, is reported to have more favourable pharmacokinetic properties thanerythromycin. Roxithromycin could, therefore, be a useful antibiotic in selected skinand respiratory infections.AcknowledgementsWe express our gratitude to C. Bebear, K. Suzaki, Y. Niitu, J. Fleurette, I. D. Farrell,A. Bure, J. Acar, J. Orfila and R. C. Spencer for their generous permission for us touse some of their data for completion of this article.ReferencesBarlam, T. & Neu, H. (1984). In vitro comparison of the activity of RU 28965, a new macrolide,with that of erythromycin against aerobic and anaerobic bacteria. Antimicrobial Agents andChemotherapy 25, 529-31.Chantot, J. F., Bryskier, A. & Gasc, J. C. (1986). Antibacterial activity of roxithromycin: alaboratory evaluation. Journal of Antibiotics 39, 660-8.Garrod, L. P. (1957). The erythromycin group of antibiotics. British Medical Journal ii, 57-63.Jones, R. N., Barry, A. L. & Thornsberry, C. (1983). In vitro evaluation of three new macrolideantimicrobial agents, RU 28965, and RU 29702, and comparisons with other orallyadministered drugs. Antimicrobial Agents and Chemotherapy 24, 209-15.Jorgensen, J. H., Redding, J. S. & Howell, W. (1986). In vitro activity of the new macrolideantibiotic roxithromycin (RU 28965) against clinical isolates of Haemophilus influenzae.Antimicrobial Agents and Chemotherapy 29, 921-2.Lyon, B. R. & Skurray, R. (1987). Antimicrobial resistance of Staphylococcus aureus: Geneticbasis. Microbiological Reviews 51, 88-134.National Committee for Clinical Laboratory Standards (1983). Methods for dilutionantimicrobial susceptibility tests for bacteria that grow aerobically. Tentative Standard M7-T. National Committee for Clinical Standards, Villanova, Pa.Rolston, K. V. I., LcBlanc & Ho, D. H. In-vitro activity of Ru 28965, a new macrolide,compared to that of erythromycin. Journal of Antimicrobial Chemotherapy 17, 161-3.Weisblum, B. (1985). Inducible resistance to macrolides, lincosamides and streptogramin type Bantibiotics: the resistance phenotype, its biological diversity, and structural elements thatregulate expression-a review. Journal of Antimicrobial Chemotherapy, 16, Suppl. A, 63-90.

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