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The spread of macrolide-resistant streptococci
in Italy
Giuseppe Cornaglia, PhD
Institute of Microbiology, University of Verona, Italy
Over the past few years, the increased frequency of infections
caused by Streptococcus pyogenes (group A streptococcus) and their sequelae has been reported in several parts
of the world (1,2). Even though these reports may reflect an enhanced awareness of and interest in these possibly
life-threatening infections on the part of the medical community (3), in at least some areas, an increase in severe
infections over time has been documented (4,5).
Meanwhile, the increased clinical use of erythromycin and its derivatives, mostly in upper respiratory tract infections,
has been related to an increased resistance of S. pyogenes to this antibiotic. Even though fewer than 5% of S.
pyogenes isolates are reported as resistant to macrolide, lincosamide, and streptogramin (MLS) antibiotics (2,6),
local exceptions have been reported, and widespread S. pyogenes resistance to erythromycin has so far been reported
in Finland (over 20%) (7-8), Japan (60%) (9), and Taiwan (10).
Awareness of GAS resistance to erythromycin seems limited. Clinical microbiology laboratories rarely determine
erythromycin susceptibility on a routine basis, and only recently have erythromycin breakpoints for streptococci
other than S. pneumoniae been added in the latest National Committee for Clinical Laboratory Standards (NCCLS)
document.
Temporal trends in S. pyogenes resistance to erythromycin and clindamycin were systematically appraised on the
basis of data collected over the last 4 years from over 30 laboratories that participated in the Italian Surveillance
Group for Antimicrobial Resistance (ISGAR). A dramatic increase in the isolation of erythromycin-resistant strains
of S. pyogenes was observed. In 1993, the incidence of erythromycin-resistant strains was on average 5.1%, with
marked variations by geographic area. Two years later, the incidence of these strains had registered a 1.5- to
roughly 20-fold increase, with a mean value of 25.9%, exceeding 40% in three centers out of 13 and 30% in another
four (11). Thus, the main surge occurred between 1994 and 1995, but the phenomenon began to manifest itself earlier
and is still decidedly on the increase in many areas. Two years after we first pointed out the dramatic increase
in the isolation of erythromycin-resistant strains of S. pyogenes in Italy, this type of resistance is widespread
in Europe (observations from Spain, France, Austria, and Russia, in addition to the pre-existing Finnish epidemic),
but the resistance rates recorded for the individual centres and the overall national resistance rate (roughly
40% in 1996) still place the resistance levels observed in Italy among the highest ever measured world-wide. The
resistance always affects the new macrolide compounds azithromycin, clarithromycin and roxithromycin.
Molecular typing results show a very substantial heterogeneity of erythromycin-resistant isolates by combining
the PFGE-type and the serotype. 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.
Only in a minority of cases, ranging from 10 to 30%, the resistance applies to all macrolides except for the 16-membered
compounds, but not to the lincosamides. In these instances, it would appear to be often related to the so-called
"M" phenotype, recently linked to the active efflux of antibiotic from the bacterial cell, as investigated
by PCR performed using the oligonucleotide primers derived from the published sequence of the ermAM gene.
Even though no cases of S. pyogenes resistance to beta-lactams have been reported, the emergence of macrolide resistance
in S. pyogenes raises important questions as to whether, and to what extent, we should be concerned about antimicrobial
resistance patterns in this species and in the entire Streptococcus genus, too.
Macrolide resistance among penicillin-resistant S. pneumoniae is a common feature, but these compounds are usually
reported as being highly active in vitro against the penicillin-susceptible strains. There are, however, some exceptions,
and in France, where prescription of macrolides was particularly high for many years, the percentage of erythromycin-resistant
S. pneumoniae was reported to be quite high (18%) in penicillin-susceptible strains, too.
Following the dramatic increase in the isolation of erythromycin-resistant strains of S. pyogenes we described
in Italy, which was also related to an abnormally high prescription of macrolides, we looked for a similar feature
in S.pneumoniae, too. Against a background of a very low rate of penicillin-resistance (less than 2% of highly
resistant strains), 829 pneumococci collected over the period 1996-97 proved resistant to erythromycin in 24.3%
of cases (22.5% in hospitalized children). This percentage rose to 27% in outpatients (whatever the age) and to
26.5% in pneumological patients. Erythromycin-resistant S.pneumoniae were uniformly cross-resistant to other macrolides.
These results show that even though pneumococcal resistance to penicillin is not yet widespread in Italy, resistance
to macrolides should be regarded as a major cause of concern.
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