Cornaglia G, Huovinen P. 1998. Macrolide resistance in Streptococcus
in Europe. APUA
table of contents
|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
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 While these data stem from scattered and mostly unpublished observations, and are obviously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.
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.
In 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.
All 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.
The 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).
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