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Medicina (Buenos Aires)

versión On-line ISSN 1669-9106

Medicina (B. Aires) v.64 n.2 Ciudad Autónoma de Buenos Aires mar./abr. 2004

 

Erythromycin-Resistant Streptococcus pyogenes in Argentina

Horacio A. Lopardo1, Claudia Hernandez1, Patricia Vidal1, Miryam Vazquez2, Liliana Rosaenz3, Gabriela Rubinstein4, Jorgelina Smayevsky5, Marta Tokumoto6, Adriana Fernandez Lausi7, Omar Daher8, Sara Kaufman9, Silvia V. Soriano10, Susana Brasili11,Marina Bottiglieri12, Maria Cristina Carranza13

1Servicio de Microbiología. Hospital de Pediatría Prof. Dr. Juan P. Garrahan, Buenos Aires;
2Hospital de Niños Dr. Ricardo Gutiérrez, Buenos Aires,
3Hospital Pediátrico Dr. Humberto Notti, Mendoza, Provincia de Mendoza;
4Hospital Ramón Carrillo y Sanatorio San Carlos, Bariloche, Provincia de Río Negro;
5CEMIC , Buenos Aires;
6Fundación Favaloro, Buenos Aires,
7Hospital Alejandro Posadas, Haedo, Provincia de Buenos Aires;
 8Hospital Zonal de Esquel, Esquel, Provincia de Chubut;
9 Hospital Juan Fernández, Buenos Aires;
10Policlínico Neuquén,  Neuquén, Provincia de Neuquén;
11Hospital Bouquet Roldán, Neuquén, Provincia de Neuquén;
12Clínica Reina Fabiola, Córdoba, Provincia de Córdoba;
13Hospital Area de Cipolletti, Provincia de Río Negro. República Argentina

Dirección postal : Dr. Horacio Lopardo, Servicio de Microbiología, Hospital de Pediatría Prof. Dr. Juan P. Garrahan, Combate de los Pozos 1881, 1245 Buenos Aires, Argentina. Fax: (54- 11) 4308 5325. e-mail: hlopardo@garrahan.gov.ar

Abstract
Erythromycin (ERY) resistance in  Streptococcus pyogenes has recently emerged as a problem of growing concern all through the world. We are presenting the comparison of results of the continuous surveillance of erythromycin resistance in S. pyogenes performed since 1989 in the Hospital de Pediatría J.P.Garrahan of Buenos Aires City, with independently observed rates in other five centers of Buenos Aires and seven centers of six other Argentinian cities, obtained between 1999 and 2001. A significant increase of erythromycin resistance was observed among S. pyogenes isolated in the Hospital Garrahan (6.6% in 1998-1999 to 9.9% in 2000). Similar trends were also detected in other centers of other Argentinian cities when recent data were compared to results of a multicenter study performed in 1995. However, lower rates of resistance were recorded in Mendoza, Cipolletti and Neuquén in comparison with data of 1995, 1998 and 1998 respectively. The reason of such decreasing resistance rates deserves to be investigated. The average of ERY-resistance rates obtained in the surveyed centers was 6.7% (range 0.5 - 14.1%). Control of antimicrobial use should be performed to warrant the future effectiveness of macrolide antibiotics regarding the positive association between use and resistance. These results  also suggest that susceptibility tests for macrolides should be performed whenever S. pyogenes is isolated in Argentina.

Key words: Erythromycin; Streptococcus pyogenes; Group A streptococci; Macrolides; Resistance

Resumen
Resistencia a la eritromicina en  Streptococcus  pyogenes en la Argentina.
La resistencia a la eritromicina en Streptococcus pyogenes ha emergido en los últimos tiempos como un problema creciente en todo el mundo. En este trabajo se presenta la comparación de los resultados de la vigilancia continua de la resistencia a la eritromicina que se viene realizando en el Hospital de Pediatría J.P.Garrahan de Buenos Aires desde 1989, con resultados independientes de otros cinco centros de la ciudad de Buenos Aires y siete de otras seis ciudades argentinas, obtenidos entre 1999 y 2001. Se observó un aumento significativo en el Hospital Garrahan (6.6% en 1998-1999 a 9.9% en el año 2000) y una tendencia similar en otros centros de diversas ciudades argentinas si se comparan estos datos con los de un estudio multicéntrico realizado en 1995. No obstante, se registraron menores porcentajes de resistencia en Mendoza, Neuquén y Cipolletti, en relación a lo hallado en 1995, 1998 y 1998 respectivamente. La razón de esta disminución merece ser investigada. El porcentaje promedio de resistencia a eritromicina obtenido en los distintos centros participantes de este estudio fue de 6.7% (rango 0.5-14.1%). Debe efectuarse un control en el uso de estos antibióticos para garantizar la efectividad futura de los macrólidos, teniendo en cuenta la asociación estrecha entre uso y resistencia. Estos resultados sugieren que deberían realizarse pruebas de sensibilidad a los macrólidos para todos los aislamientos de S. pyogenes en la Argentina.

Palabras clave: Eritromicina; Streptococcus pyogenes; Estreptococos grupo A; Macrólidos; Resistencia

Erythromycin (ERY) has been extensively used in the management of pediatric infections since it was discovered in 1952. Mainly, it is alternative in cases of penicillin allergy or in infections due to penicillin-resistant organisms. Macrolide use was enhanced by the recent introduction of new compounds with better pharmaco-kinetic properties, gastrointestinal tolerability and decreased interactions with commonly used drugs.
ERY-resistant group A streptococci (ERGAS) have already been described in several countries from different continents in rates higher than 10%1-3. However in some cases the problem disappeared as macrolide use diminished3. Overuse of macrolides was identified as the main cause of resistance increase1, 3-5. There are two well-characterized mechanisms that may be responsible of such resistance in beta-hemolytic streptococci: target site modification (ribosome methylation) and active drug efflux6, 7.
     ERY resistance in S. pyogenes was recognized as a rare event in Argentina by 1994. Macrolide resistance may be due to either inducible or constitutive 23S ribo-somal dimethylation (MLSB), active efflux (M phenotype) or modification of protein L4 or RNA sequences by mutation. MLSB may be coded either by the ermTR gene (now classified as an ermA variant) or by the ermB gene. Active efflux is coded by mefA or mefE genes in streptococci. Only few isolates showing an inducible MLSB phenotype were obtained during 19898. Fifty eight centers from 27 Argentinian cities participated in two monthly studies on prevalence of ERY susceptibility of S. pyogenes. Prevalences of 0.14% (1 isolate) and 0.28% (3 isolates) in May and October 1994 were respectively observed from a total of 1767 (713 and 1054) tested isolates9. Three isolates showed the MLSB phenotype, two of them having the ermTR gene and one strain had the efflux mechanism (M phenotype coded by mef A gene)10.
     Later, in 1995, 11.1% (15/135) of resistant isolates have been reported in Mendoza9 and 12% (30/251) in 1998 in Neuquén and Cipolletti11. All those resistant isolates showed the M phenotype. Some of them were characterized as having the mefA gene10.
     We are describing now the evolution of erythromycin resistance in S. pyogenes isolated in one pediatric hospital of Buenos Aires comparing these results with independently observed rates in other five centers of Buenos Aires and seven centers of six other Argentinian cities.  
     Isolates obtained from pharyngeal exudates of children hospitalized or assisted as outpatients in any of the 13 centers were identified primarily by pyrrolidonyl aryla-midase and bacitracin tests. Doubtful results were confirmed by serological tests, Voges-Proskauer and Rapid ID32 profiles (bioMérieux, Marcy l’Étoile, France) at the Hospital de Pediatría Prof. Dr. Juan P. Garrahan12.
     Susceptibility tests for ERY and clindamycin (CLI) were performed by the double disc method in 5% sheep blood  Mueller Hinton agar11. Susceptibility to penicillin (PEN), ceftriaxone (CRO), ERY, CLI and azithromycin (AZI) of ERGAS isolated in the Hospital de Pediatría Prof. Dr Juan P. Garrahan were tested by the agar dilution method following National Committee for Clinical Laboratory Standards (NCCLS) guidelines13. ERGAS were defined as ERY non-susceptible S. pyogenes (zone < 21mm).
     Eight hundred and eighty four isolates of S. pyogenes were obtained from 4474 pharyngeal exudates during one year (August 1998 - July 1999). Fifty eight of them (6.6%) were ERGAS. Eighteen ERGAS were tested by the dilution method. Minimal inhibitory concentrations (MICs) ranges in µg/ml were: PEN (<0.007-0.015), CRO (<0.007), ERY (4-16), CLI (<0.06-8) and AZI (32-64). Most of ERGAS (94.4%) had an M phenotype suggesting that an efflux mechanism was involved. Only one isolate (5.6%) was recognized as having the MLSB inducible susceptibility pattern.
     Seven hundred and forty two group A beta-hemolytic streptococci out of 772 isolated from 4.942 pharyngeal exudates during 2000 in the same hospital were studied in the same way.
     Higher rates of ERGAS (9.9%) were observed in this instance as compared with those of 1988-89 (6.6%) (chi square, P = 0.01). A comparison with recent data from other Argentinian cities is presented in Table 1. ERY resistance range was 3.3-14.1% in the period 1998-2001 for the Buenos Aires area (average = 7.7%). In six other cities the range was 0.5 - 12% (average = 5.8%). Range in all the country was 0.5-14.1% (average 6.7%).

Table 1.– Erythromycin resistance in different Argentinian centers (1998-2001)

     Concluding, a significant increase of ERY resistance was observed among S. pyogenes isolated in one pediatric hospital of Buenos Aires. Similar trends were also detected in other centers of other Argentinian cities when recent data were compared to previous results of a multicenter study (9). However, lower rates of ERGAS were recorded in Mendoza, Cipolletti and Neuquén in comparison with data of 1995, 1998 and 1998 respectively. The reason of such decreasing resistance rates deserves to be investigated.
     The average of ERY-resistance rates obtained in the surveyed centers was 6.7% (range 0.5-14.1%). Control of antimicrobial use should be performed to warrant the future effectiveness of macrolide antibiotics regarding the possitive association between use and resistance, as previously was demonstrated in Finland3.
     These results also suggest that susceptibility tests for macrolides should be performed whenever S. pyogenes is isolated in Argentina. Monitoring susceptibility rates will eventually lead to rationale recommendations for treating upper respiratory infections.

References

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Received: 11-08-2003
Accepted: 2-12-2003