CITATION: Cornaglia G, Huovinen P. 1998. Macrolide resistance in Streptococcus pyogenes in Europe. APUA Newsletter 16(4): 1-2,4-6.

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Macrolide resistance in Streptococcus pyogenes in Europe
Giuseppe Cornaglia, Pentti Huovinen and the European GAS Study Group
University of Verona, Verona, Italy and NIH, Turku, Finland

In the late eighties and early nineties, Europe witnessed two major epidemics of macrolide resistance in
Streptococcus pyogenes isolates. The first occurred in Finland beginning in 1988, and was mainly related to phenotype M (i.e., an efflux mechanism) or inducibile MLS (macrolide-lincosamide-streptograminB) phenotype. This led to a maximum percentage of resistant isolates of up to 42% that then declined significantly after a nationwide reduction in macrolide consumption. The second epidemic occurred in Italy beginning in 1993 and was mainly related to the constitutive MLS phenotype. This epidemic led to a mean percentage of resistant isolates of roughly 40%, and is still decidedly on the increase in some areas of the country. Both epidemics were related to the increased macrolide consumption in the respective countries.
To track antibiotic resistance, a European network for resistance of group A streptococci (GAS) was established and has collected resistance data from different areas in Europe during 1997-98. Macrolide resistance in streptococci is becoming an important issue all over Europe and we were interested in plotting the first comprehensive map of this problem in Europe and determining both the resistance rates and the prevailing phenotypes.

At the WHO Workshop, "The Current Status of Antimicrobial Resistance Surveillance in Europe" held in Verona, Italy in December, 1997, macrolide resistance was identified as a good model for sharing information on the current status of antimicrobial resistance surveillance, for exploring data-sharing options and for defining possible collaborative activities. As a result, workshop participants were later asked to kindly provide us with the most up-to-date information about macrolide resistance in
S. pyogenes which, to the best of their knowledge, was available in their country, and to let us know whether their colleagues could provide additional - or more updated - data. The individual country data are reported below without any omission or deletion and all contributions are fully acknowledged in the text. While these data stem from scattered and mostly unpublished observations, and are obviously uneven, they were mostly provided by National Institutes for Health, Reference Centers for streptococci, multicenter studies and/or renowned experts in the field. Thus they probably represent the best information available in many European countries and can contribute to drafting a rough map of Europe, showing the different levels of resistance.

The map summarizes the ranges of reported rates of erythromycin resistance for the various European countries in 1997-1998 (Figure 1). Macrolide resistance seemed virtually absent in Iceland and very limited in other countries in Northern Europe - except Finland - and in Ireland. In addition, resistance was reportedly absent in Romania and occurred in less than 5% in most other countries of Eastern Europe with the very remarkable exceptions of the Baltic Republics (especially Lithuania), and Ukraine. In the only two countries of former Yugoslavia for which data could be obtained, resistance rates were below 5% in Slovenia, whilst they seemed to exceed 10% in Croatia. Slovakia, Hungary, and Russia reported midlevel resistance rates ranging from 5 to 15%. Similar resistance levels (5 to 15%) were also reported in Western and Central Europe, with slightly higher values in Austria.

In Southern Europe, Italy reported the highest percentage of resistant strains (roughly 40%), although values over 25% have also recently been reported from Greece, Spain and Portugal. Surprisingly, the only country - apart from a number of countries of the Balkans or former Soviet Union - for which we were unable to obtain data, despite several attempts at the highest level, was the largest country in Europe, namely Germany.

What emerges from this survey is the scarcity of available information about the resistance phenotype (even though some data about clindamycin resistance seem to show that the M phenotype prevails in most countries), and the extreme scarcity of molecular studies performed to date. In many countries, even the need for testing macrolide susceptibility in
S. pyogenes is still virtually ignored. It is our hope that the map we have presented will stimulate awareness of the situation, prompt further studies for both a wider and deeper appreciation of this new problem in the epidemiology of resistance and promote continued international collaboration to address it.

Of a total of 120 strains isolated in the Elisabethinen Hospital Linz (Upper Austria), 14 (12%) had an MIC of >4 µg/ml for erythromycin (H.Mittermayer, p.c.; C.Jebelean et al., 20th ICC, Sydney, Australia, Abs. 4306). Most of the resistant strains were sensitive to lincomycin, apparently showing the M phenotype. In a study performed at the University of Graz, 53 out of 248
S. pyogenes strains (21.4%) showed resistance to erythromycin. All these strains showed the M resistance phenotype in the erythromycin-lincosamide disc induction test (A.Grisold et al., 8th ECCMID, Lausanne 1997, Abs P1185).

The National Reference Center for Group A Streptococci tested 2,050
S. pyogenes , collected since 1993 from all over the country, for erythromycin resistance (Herman Goossens et al., 38th ICAAC, San Diego, 1998): 163 (8.0%) of the strains were erythromycin-resistant, and most of them (77.9%) showed active efflux (as confirmed by PCR, too).

WHONET data (Boyka Markova, p.c.) were collected over the years at the Alexander University Hospital, Medical University of Sofia and at the Medical University of Pleven.

In 1997-98, the rates of azithromycin resistance in Zagreb were 9% in the ÎFran Mihaljevicâ Clinical Hospital (Natasa Sterk-Kuzmanovic, quoted by Smilja Kalenic, p.c.) and 15.3% in the Dubravaâ Clinical Hospital (Jasenka Subic-Skrlin, as above), respectively.

Czech Republic
The National reference laboratory for antibiotics (JiÈÕ Schindler and Pavla UrbaÎková, p.c.) reports that macrolide resistance, which was rare before 1996 (0.2% in 1990) seems to be slowly rising. Data collected from 10 geographically different regions show mean incidences of 3.3% in 1996 (max 6.6%) and 2.7% in 1997 (max 6.5%). Roughly 70% of the erythromycin-resistant strains were resistant to clindamycin, too.

S. pyogenes isolated from throat swabs the macrolide resistance frequencies are 1.6% (1997). In all isolates, including invasive isolates, the resistance is 0.8% (Thomas Lund Sorensen, Statens Serum Institut, p.c.).

Estonia so far lacks a comprehensive surveillance network for macrolide resistance of
S. pyogenes. Moreover, erythromycin resistance is not always tested in routine laboratory practice because penicillin has remained the drug of choice for group A streptococci, and the consumption of new macrolides is almost nil. Therefore, only limited data are available about macrolide resistance. In 1998, susceptibility to erythromycin was tested in a total of 575 S. pyogenes isolated in three clinical laboratories from throat-swabs (mainly), pus and blood samples (Tonis Karki, p.c.). The frequency of resistance to erythromycin was in all, 10.4 % (60 strains) of isolates were resistant and 12.4% (71 strains) intermediate to erythromycin, making a total of 22.8% non-susceptible strains.

In 1997 the Finnish Study Group for Antimicrobial Resistance studied a total of 5662 group A streptococci of which 3.1% (N=175) were resistant and 6.6% (N=371) intermediate. Thus R+I together were 9.6% (Pentti Huovinen, p.c.).

A national survey of
S. pyogenes invasive infections was performed in 1995. Data were sent by 98 hospitals located in 59 regions of France. Erythromycin resistance was found in 5.2% of all the 290 strains tested and in 9.8% of the 122 blood cultures isolated (Anne Bouvet, p.c.; E.Varon and the Groupe dâEnquête 1995 sur les Infections Streptococciques, Adv. Exp. Med. Biol. 418:229-231, 1997). The 1997-98 data from Hotel Dieu Hospital in Paris show 7.1% of erythromycin-resistant strains isolated from adult patients (Anne Bouvet, p.c.).

The percentages of resistance to erythromycin in
S. pyogenes in the Penteli Childrenâs Hospital (Athens) were 5% up to 1994 and 8% in 1995 (Alkiviadis Vatopoulos, p.c.). Out of 505 S. pyogenes strains isolated from two of the Athens Childrenâs Hospitals (Aghia Sofia and Aglaia Kyriakou) in the first semester of 1998, 97 proved resistant and 35 intermediate, making a total of 26.1% (Nikolaos-Stefanos J. Legakis, p.c.).

Resistance data of
S. pyogenes to macrolides (1997) were summarized at the National Institute of Public Health and at the St.László Hospital in Budapest (Marianne Konkoly Thege and Anna Marton, p.c.). The isolates from Hungarian hospitals proved resistant in 4.2% of cases and intermediate in 5%, making a total of 9.2% of non-susceptible strains. The isolates from laboratories of the Hungarian Public Health network proved resistant in 1.7% of cases and intermediate in 2.6%, to a total of 4.3% of non-susceptible strains.

S. pyogenes isolates tested in Iceland have been uniformly sensitive to erythromycin until July 1998, thus the microbiologists of this country have not been doing routine susceptibility tests on these organisms (except for invasive isolates). The first strain of S. pyogenes with resistance to macrolides was isolated from an immigrant worker (who may have imported the strain) and was picked up since it was an invasive isolate (blood). Whether to start doing susceptibility tests on all isolates in Iceland (i.e. including all throat isolates) is under consideration (Karl G. Kristinsson, p.c.).

Absolute information could not be obtained, but macrolide resistance in Dublin is commonly held to be fairly limited. For the St. Jamesâs Hospital, the resistance rate for erythromycin is 3%, (Conor Keene, p.c.), and similar rates are reported by Mary Cafferkey (p.c.) at the Rotunda Hospital, whilst in the Beaumont Hospital no resistant strains have so far been isolated (Ed Smyth, quoted by Conor Keene, p.c.).

A dramatic increase in the isolation of erythromycin-resistant strains of
S. pyogenes was pointed out in 1995 by the Italian Surveillance Group for Antimicrobial Resistance (ISGAR). The resistance, whose main surge occurred between 1994 and 1995, is still decidedly on the increase in many areas, and the resistance rates recorded for the individual centres and the overall national resistance rate (roughly 40% in 1997) still place the resistance levels observed in Italy among the highest ever measured world-wide. Unlike the experience in other countries, more often than not the resistance is not confined to the 14- and 15-membered macrolides only, but affects the 16-membered compounds and the lincosamides, too. Thus, it would appear to depend on the active efflux of antibiotic from the bacterial cell (the so-called ãMä phenotype) only in a minority of cases (G.Cornaglia and ISGAR, Emerg. Inf. Dis. 2:339-342, 1996; Clin. Inf. Dis., 27(Suppl.1), 1998).

The National Environmental Health Center (Ivonna Selga, p.c.) reports data limited to the antimicrobial susceptibility of
S. pyogenes strains isolated in the Childrenâs Hospital of Latvia throughout 1997. Out of 30 strains, all from specimens other than throat swabs, three (10%) proved non-susceptible to erythromycin.

S. pyogenes susceptibility to erythromycin in three laboratories in Vilnius in 1997 has been summarized by Petras Kaltenis (p.c.):
On average, the non-susceptible strains were 50.2% of the total examined (327).

In the Netherlands in 1997 1.5% of 2,449
S. pyogenes isolates tested at the S-breakpoint (1 mg/L) were erythromycin-resistant. This is the result of an ongoing electronic resistance surveillance in nine Dutch Public Health laboratories (Hanú de Neeling, p.c.). Very low resistance rates also stem from erythromycin resistance data of 341 S. pyogenes isolates from the University Hospital in Utrecht (Ellen M. Mascini, Jan Verhoef) over the period 1994-1997.

The lab at Akershus central hospital (Martin Steinbakk, p.c.) tested 232 clinical isolates of
S. pyogenes for erythromycin resistance in 1997. Only one isolate was found to be resistant and a further four had reduced sensitivity (R+I=2.1%), the other 227 isolates being fully susceptible. None of 7 blood culture isolates were resistant. Only one isolate resistant to clindamycin was found (the erythromycin resistant isolate was fully susceptible to clindamycin). The National Institute of Public Health is at present unable to provide updated data as to the situation on macrolide resistance in Norway. However, Dr. Høiby has a collection of nearly 80% of all systemic isolates of GAS and has just started screening for macrolide resistance, confirming that the actual level of resistance is very low.

The Sera and Vaccines Central Research Laboratory (National Reference Center for Antimicrobial Susceptibility) reports that of 120
S. pyogenes strains isolated in the whole country from skin and soft tissue infections, five were resistant to erythromycin and one was intermediate. The data on tonsillitis isolates (same source) confirmed a 5% incidence of erythromycin-resistant strains in Poland (Waleria Hryniewicz, p.c.).

In 1997 and 1998,
S. pyogenes from children attending day-care centers in Lisbon were studied. The antibiotic resistance patterns obtained are considered of great concern since 31% of the isolates were resistant to erythromycin, 35% were resistant to azithromycin and 29% to clarithromycin. Oral penicillin is not commercially available in Portugal, and erythromycin is usually the antibiotic of choice for treating infections caused by S. pyogenes (Hermínia De Lancastre, p.c.).

So far, in this country, group A,C,G hemolytic streptococci have been tested for susceptibility to the following antibiotics by the diffusion method: penicillin, erythromycin, chloramphenicol, vancomycin, ofloxacin, rifampin, cephalothin, ceftriaxone. As far as is known, no erythromycin resistance was revealed to
S. pyogenes (M.Pana and M.Ghita, p.c.).

Clinical strains of
S. pyogenes collected in 1994-96 in Smolensk (total=101 isolates) proved resistant in 9.7% of cases and intermediate in 2.9%, making a total of 12.7% non-susceptible strains; in contrast, only 1.9% of the same strains were resistant to clindamycin (L.Stratchounski et al., 37° ICAAC, Toronto, Canada, Abs. C-71).

Resistances rates ranging from 3.5 to 5.5% are reported for 1997, the highest values being reported in Western Slovakia (Vladimir KrFmery, p.c.). A National monitoring study starts in September â98, and comprehensive data are expected in January â99 (Leon LangÎádl, p.c.).

Data about the susceptibility to macrolides in
S. pyogenes were collected over the years at the Institute of Microbiology and Immunology, Medical Faculty, Ljubljana (Katja Sem, Marija Gubina and Milan ái*man, p.c.).

During the period 1984-1996, 2,561
S. pyogenes were studied in Gipuzkoa (Emilio Perez-Trallero et al., Eur. J. Clin. Microbiol. Inf. Dis. 17:25-31, 1998). Until 1990, only 1.2% of isolates were resistant to erythromycin. Since then, this frequency increased every year up to 1995, when 34.8% of isolates were resistant to erythromycin. The rate of S. pyogenes resistance to erythromycin was 17.8% in 1996 and 13.7% in 1997. During the study period, 96.1% of the isolates resistant to erythromycin were clindamycin susceptible. The same group studied 1,310 strains collected in the city of Madrid from January 1993 through December 1996 (B.Orden et al., Ped. Inf. Dis. J. 17, June 1998). Resistance to erythromycin showed a sharp increase during the study period (2.0% in 1993 versus 22.4% in 1996). Only 5 of the 126 erythromycin-resistant S. pyogenes isolated in 1996 displayed the MLSb phenotype. To assess the overall prevalence of erythromycin resistance in the country, the Spanish Surveillance Group of Respiratory Pathogens (SSGRP) studied 866 S. pyogenes isolated from 14 Spanish hospitals and collected from May 1996 through April 1997 (F.Baquero, p.c.; J.Garcia de Lomas et al., 2nd ECC, Hamburg 1998, Abs. T 267).

According to data from The Swedish Institute for Infectious Disease Control and the Swedish Reference Group for Antibiotics, collected from 30 laboratories (100 strains/lab/year), the incidences of resistance are as follows (Barbro Olsson-Liljequist, p.c.):

At the University Hospital, Lausanne, macrolide resistance increased from 2% in 1995 to 10% in 1997 (Jacques Bille, p.c.). Data from the University Hospitals of Switzerland and several private laboratories (collected by R.Auckentaler, p.c.) yielded rates ranging from 3% to 15%, and exceeding 10% in 5 out of 8 centers.

The susceptibility to erythromycin was tested in 378 strains isolated in 1998 in three institutes and two medical centers of Kiev. The results were collected at the Institute of Epidemiology and Infectious Diseases (Anatoly Shapiro, p.c.). On average, the incidence of non-susceptible strains was 43.3%, ranging from 25-30% (Institute of Epidemiology & Inf. Dis. and Main Military Clinical Hospital, where most patients were outpatients) to as much as 65-70% (Antisepsis Center and Institute of Neurosurgery).

United Kingdom
The most recent (1996) published rate for invasive S. pyogenes strains was 17%. This is based on tests done by Rob George (quoted by David Livermore, p.c.) at the Streptococcal Reference Unit, Central Public Health Laboratory. Based on reports sent to CPHL from blood isolates last year (not tested there) the rate was 7.3%. Data for S. pyogenes isolates from all sources in the West Midlands (Dept. of Medicine Management Report, University of Keele, aided by Rod Warren) indicate a rate of about 10% last year. Data from the City Hospital, Birmingham, based on 198 different non-duplicate isolates, show that erythromycin resistance was 11.6% (Richard Wise, p.c.).


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