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Antimicrobial Agents and Chemotherapy, September 2002, p. 2963-2968, Vol. 46, No. 9
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.9.2963-2968.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Antistreptococcal Activity of Telithromycin Compared with Seven Other Drugs in Relation to Macrolide Resistance Mechanisms in Russia

Roman S. Kozlov,¹ Tatiana M. Bogdanovitch,¹ Peter C. Appelbaum,² Lois Ednie,² Leonid S. Stratchounski,¹ Michael R. Jacobs,³ and Bülent Bozdogan^2*

Institute of Antimicrobial Chemotherapy, Smolensk, Russia,¹ Department of Pathology, Hershey Medical Center, Hershey, Pennsylvania,² Case Western Reserve University, Cleveland, Ohio³

Received 7 January 2002/ Returned for modification 16 April 2002/ Accepted 17 May 2002

Top Abstract Introduction Materials and Methods Results Discussion References

 
The susceptibilities of 468 recent Russian clinical Streptococcus pneumoniae isolates and 600 Streptococcus pyogenes isolates, from 14 centers in Russia, to telithromycin, erythromycin, azithromycin, clarithromycin, clindamycin, levofloxacin, quinupristin-dalfopristin, and penicillin G were tested. Penicillin-nonsusceptible S. pneumoniae strains were rare except in Siberia, where their prevalence rate was 13.5%: most were penicillin intermediate, but for three strains (two from Smolensk and one from Novosibirsk) the MICs of penicillin G were 4 or 8 µg/ml. Overall, 2.5% of S. pneumoniae isolates were resistant to erythromycin. Efflux was the prevalent resistance mechanism (five strains; 41.7%), followed by ribosomal methylation encoded by constitutive erm(B), which was found in four isolates. Ribosomal mutation was the mechanism of macrolide resistance in three isolates; one erythromycin-resistant S. pneumoniae isolate had an A2059G mutation in 23S rRNA, and two isolates had substitution of GTG by TPS at positions 69 to 71 in ribosomal protein L4. All S. pyogenes isolates were susceptible to penicillin, and 11% were erythromycin resistant. Ribosomal methylation was the most common resistance mechanism for S. pyogenes (89.4%). These methylases were encoded by erm(A) [subclass erm(TR)] genes, and their expression was inducible in 96.6% of isolates. The rest of the erythromycin-resistant Russian S. pyogenes isolates (7.6%) had an efflux resistance mechanism. Telithromycin was active against 100% of pneumococci and 99.2% of S. pyogenes, and levofloxacin and quinupristin-dalfopristin were active against all isolates of both species.

Top Abstract Introduction Materials and Methods Results Discussion References

 
The problem of pneumococcal strains resistant to ß-lactams, macrolides, and other compounds has spread worldwide to such a degree that we are in the midst of a pandemic (9). Across the world, the incidence of pneumococcal strains that are fully resistant to penicillin G is rising relative to strains with intermediate penicillin resistance (1, 6, 10; A. L. Barry, P. C. Fuchs, and S. D. Brown, Letter, J. Antimicrob. Chemother. 40:139-140, 1997). The problem is complicated by the fact that the higher the penicillin G MIC for pneumococci is, the higher the prevalence of macrolide resistance is. In the United States, <5% of pneumococcal strains susceptible to penicillin G are macrolide resistant, while approximately 30% of penicillin-intermediate and >50% of penicillin-resistant strains are macrolide resistant (11). This relationship between penicillin G and macrolide resistance is not the same in all countries. For example, approximately 50% of Spanish strains with intermediate resistance to penicillin G are macrolide resistant, and in Northern Italy, where the rate of penicillin resistance is approximately 5%, 45% of penicillin-susceptible strains are resistant to macrolides (3). Pneumococcal strains resistant to ß-lactams are a particular problem in Central and Eastern Europe, especially in Hungary, Slovakia, Romania, and Bulgaria (2).

Although Streptococcus pyogenes strains have not yet developed resistance to penicillin G, macrolide resistance in these strains is quite widespread throughout the world, particularly in Europe (3, 4, 8, 17). Although the prevalence of macrolide resistance in the United States has been described as being low (12), a recent report has described an increase in macrolide resistance in the San Francisco Bay area (24).

High prevalence of erythromycin resistance in pneumococci and group A streptococci in many Central and Eastern European countries has already been documented by our group (14, 15).

Macrolide resistance among Streptococcus pneumoniae and S. pyogenes is usually because of the ribosomal methylation of 23S rRNA [erm(B) or erm(A)] or active efflux of these antibacterials [mef(A)] (21). Recently, ribosomal mutations in 23S rRNA and ribosomal L4 proteins that confer macrolide resistance were described in clinical strains of S. pneumoniae (7, 23).

This study compared the activity of telithromycin with activities of erythromycin, azithromycin, clarithromycin, clindamycin, penicillin G, quinupristin-dalfopristin, and levofloxacin against S. pneumoniae and S. pyogenes organisms from centers throughout the Russian Federation. Macrolide resistance mechanisms of erythromycin-resistant isolates were determined.

Top Abstract Introduction Materials and Methods Results Discussion References

 
Bacteria and antimicrobials. Isolates were isolated consecutively from the various centers during 2000 and 2001 and were screened using optochin and bacitracin disk methodology. For the purpose of this study, the Russian Federation was divided into five regions: (i) central (Moscow, Kazan, Ryazan, Nizhnij Novgorod, and Yaroslavl); (ii) northwest (Smolensk and St. Petersburg); (iii) south (Krasnodar); (iv) Urals (Ekaterinburg and Chelyabinsk); and (v) Siberia (Tomsk, Irkutsk, Tumen, and Novosibirsk) (Fig. 1). Organisms were then transported to Hershey Medical Center, Hershey, Pa., where they were stored frozen in double-strength skim milk (Difco Laboratories, Detroit, Mich.) at -70°C until use. Before testing, S. pneumoniae and S. pyogenes cultures were checked for purity. The identity of S. pneumoniae strains was confirmed by optochin and, as necessary, by bile solubility testing. The confirmation of identity of S. pyogenes was done by bacitracin disk (Becton Dickinson, Cockeysville, Md.) and, as necessary, by latex agglutination. Telithromycin, quinupristin-dalfopristin, levofloxacin, erythromycin, azithromycin, and clarithromycin were obtained from Aventis Pharma, Infectious Division, Romainville, France. Clindamycin and penicillin G were purchased from Sigma Inc., St Louis, Mo.

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FIG. 1. Geographic locations of Russian centers providing S. pneumoniae and S. pyogenes isolates for this study.

Susceptibility testing. Susceptibility testing was performed by agar dilution on Mueller-Hinton agar (Difco) supplemented with 5% sheep blood (6, 16). Inocula were prepared by suspending growth from overnight cultures in sterile Mueller-Hinton broth to a turbidity equal to a 0.5 McFarland standard. A 1:10 dilution was made in Mueller-Hinton broth so that the final inocula contained 5 x 10⁴ CFU/spot. Plates were inoculated with a Steers replicator using 3-mm-diameter inoculating pins, delivering 1 µl of inoculum, and incubated overnight at 35°C in air (5, 18). The lowest concentration of antimicrobial showing no growth was read as the MIC. Standard quality control strains, including Staphylococcus aureus ATCC 29213 and S. pneumoniae ATCC 49619, were included with each run. Breakpoints used were those approved by the National Committee for Clinical Laboratory Standards for S. pneumoniae and S. pyogenes (16) except for telithromycin, for which European breakpoints were used: susceptible, 0.5 µg/ml; intermediate, 1.0 to 2.0 µg/ml; and resistant, >2 µg/ml (C. J. Soussy, F. Goldstein, A. Bryskier, H. Drugeon, J. Andrews, F. Baquero, O. Cars, D. Felmingham, B. Olsson-Liljequist, A. Rodloff, G. C. Schito, B. Wiedemann, and R. Wise, Abstr. 40th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 321, 2000).

Determination of macrolide resistance mechanisms and gene sequencing. Isolates found to be resistant to macrolides were screened for their resistance mechanisms. Primers and PCR conditions used for this work have been described previously: those for mef(A) and erm(B) were described by Sutcliffe et al. (21), those for erm(A) were described by Pankuch et al. (19), and those for 23S rRNA and L4 protein genes were described by Tait-Kamradt and coworkers (22, 23). The PCR products after amplification of domain V of 23S rRNA, and entire genes encoding L4 and L22, were purified using a QIAquick PCR purification kit (QIAGEN, Valencia, Calif.) and sequenced using an Applied Biosystems model 373 DNA sequencer. All erythromycin-resistant strains were screened for the ability to induce resistance by the double-disk diffusion test using erythromycin and clindamycin disks (20).

PFGE. Pulsed-field gel electrophoresis (PFGE) was performed using a CHEF DR III apparatus (Bio-Rad, Hercules, Calif.) as described previously (13).

Top Abstract Introduction Materials and Methods Results Discussion References

 
S. pneumoniae. S. pneumoniae strains were isolated predominantly from respiratory sources (61%). Most of the pneumococci were from sputum (51%), ear (11.5%), and cerebrospinal fluid (11.1%). Patient ages varied from 1 month to 85 years. The peak age distribution was found in children 2 to 10 years old. Susceptibilities of the pneumococcal strains tested are shown in Tables 1 and 2. Raised penicillin G MICs were found at a prevalence of 5% in all regions of Russia tested except in Siberia, where the prevalence was 13.5%. In all areas, penicillin G-intermediate isolates for which the MICs were between 0.125 and 1.0 µg/ml far outnumbered penicillin G-resistant isolates for which the MICs were 2.0 µg/ml. However, three penicillin G-resistant pneumococcal isolates for which the MICs were 4.0 to 8.0 µg/ml were isolated. Two isolates from Smolensk, for which the MICs of penicillin G were 4 and 8.0 µg/ml, were from the lung tissue of a 4-month-old infant and the sinus of a 40-year-old patient, respectively; these strains were resistant to macrolides but susceptible to clindamycin and telithromycin. The other strain, for which the MIC of penicillin G was 8.0 µg/ml, was isolated from the sputum of a 30-year-old patient in Novosibirsk; this strain was susceptible to all other agents tested. The cefotaxime MICs for these three strains were all 1 µg/ml. Macrolide resistance was rare in all areas tested. All pneumococcal strains were susceptible to telithromycin, levofloxacin, and quinupristin-dalfopristin at the breakpoints used.

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TABLE 1. Agar dilution MICs of agents tested against S. pneumoniae

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TABLE 2. Rates of susceptibility of S. pneumoniae to various agentsa

The MICs of the agents tested according to resistance mechanism are shown in Table 3. Telithromycin was the most active antibacterial tested against all strains of both species, regardless of their macrolide resistance mechanism. The prevalence of erythromycin resistance among S. pneumoniae strains was 2.5% (12 isolates). Most of the macrolide-resistant S. pneumoniae were isolated from sputum (63%). The mechanisms of macrolide resistance were mef(A) (five isolates; 41.7%) and erm(B) (four isolates; 33.3%) genes and ribosomal mutations (three isolates; 25%) in ribosomal protein L4 (two isolates) and in 23S rRNA (one isolate).

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TABLE 3. MICs according to mechanism of resistance in 12 macrolide-resistant S. pneumoniae isolates

Two strains had an L4 ribosomal protein gene mutation that caused substitution of the three amino acids GTG by TPS at positions 69 to 71. Interestingly these two strains were two penicillin-resistant strains from Smolensk (northwest Russia). As seen in Fig. 2 the PFGE patterns of these strains after digestion with SmaI were similar. One strain, isolated from the pleural fluid of a 38-year-old patient in Ekaterinburg, had a mutation at position 2059 (Escherichia coli numbering system) in domain V of the gene encoding 23S rRNA, with replacement of A by G. The resistance phenotype of this strain was similar to the ML phenotype of three strains isolated in the United States and had the same mutation (23). The quinupristin-dalfopristin MIC for this isolate was 0.5 µg/ml, while the MICs of quinupristin and dalfopristin were 8 and >128 µg/ml, respectively.

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FIG. 2. PFGE pattern of three S. pneumoniae strains with ribosomal mutations after digestion with SmaI. Lane 1, strain with mutation in 23S rRNA; lanes 2 and 3, strains with mutation in ribosomal protein L4.

S. pyogenes. Although most S. pyogenes strains were isolated from the respiratory tract (69%), a number of strains, especially those from the northwest, were isolated from wounds (27%). S. pyogenes isolates were from patients 2 weeks to 81 years old. Most were isolated from children and young adults (63%).

Susceptibility patterns of S. pyogenes are presented in Tables 4 and 5. All isolates were susceptible to penicillin G. Of 600 S. pyogenes isolates tested, 66 isolates (11%) were found to be resistant to macrolides. Erythromycin resistance was mainly seen in the Siberia, northwest, and central regions. The MICs of the agents tested according to resistance mechanism are shown in Table 6. The majority of macrolide-resistant S. pyogenes strains were isolated from wound (47%) and throat (36%) specimens. Erythromycin resistance was a result of the presence of the erm(A) gene subclass erm(TR) in 59 isolates (89.4%) or the mef(A) gene in five isolates (7.6%) (Table 6). Except for two strains the expression of erm(A) genes was inducible by the double-disk method (20) (96.6%).

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TABLE 4. Agar dilution MICs of agents tested against S. pyogenes

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TABLE 5. Rates of susceptibility of S. pyogenes to various agentsa

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TABLE 6. MICs according to mechanism of resistance in 66 macrolide-resistant S. pyogenes isolates

The susceptibility rate of telithromycin was 99.2%. Five isolates (7.6%) among the 66 erythromycin-resistant S. pyogenes isolates were intermediate to telithromycin (MICs, 1 µg/ml); two had constitutive erm(A) genes and three had mef(A) genes. The MICs of erythromycin, azithromycin, and clarithromycin for two strains with constitutive erm(A) were >64 µg/ml, and those of telithromycin were 1 µg/ml.

Two strains had no known erythromycin resistance genes or mutations in genes encoding 23S rRNA or ribosomal proteins L4 or L22; these strains were from Yaroslavl (central Russia) and were isolated from throats of 22- and 40-year-old patients. For these strains, the MICs of erythromycin, azithromycin, clarithromycin, clindamycin, and telithromycin were 1, 2 to 4, 0.5 0.125, and 0.03 to 0.06 µg/ml, respectively. These strains had the same PFGE pattern after digestion with SmaI (Fig. 3). The mechanism of macrolide resistance of these strains is currently under investigation.

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FIG. 3. PFGE pattern of two S. pyogenes strains from Yaroslavl with unknown resistance mechanisms.

Among the strains with the erm(A) gene, four PFGE types containing more than one isolate were characterized. Eighty-six per cent of the erm(A) strains had one of these four PFGE patterns after digestion with SmaI (Fig. 4). Twenty-two strains were PFGE type A, 5 were PFGE type B, 6 were PFGE type C, and 18 were PFGE type D. Three isolates from Smolensk, two from Tumen, and one from Ekaterinburg had the same PFGE type; these cities are located far from each other (Fig. 1).

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FIG. 4. PFGE patterns of S. pyogenes strains with the erm(A) gene.

Top Abstract Introduction Materials and Methods Results Discussion References

 
In the present study, a very low prevalence of drug resistance was found for S. pneumoniae and S. pyogenes except in Siberia (both species) and the northwest and central regions (S. pyogenes). The pneumococci for which the penicillin G MICs were highest (4 to 8.0 µg/ml) came from Novosibirsk, a city in south central Siberia, and two strains from Smolensk. The Siberian isolate was susceptible to other drug classes, but the Smolensk strain was macrolide- and azalide-resistant, with mutation in ribosomal protein L4. The reason for these geographic differences is unclear at present but may be related to travel patterns and/or antibacterial use in the different parts of Russia. This is currently under investigation.

Irrespective of resistance to other drugs or drug classes, all pneumococci were susceptible to telithromycin, levofloxacin, and quinupristin-dalfopristin. It is noteworthy that the low prevalence of drug-resistant pneumococci and S. pyogenes in most areas of Russia parallels those found recently by our group in Baltic countries such as Lithuania and Latvia (P. C. Appelbaum et al., Abstr. 40th Intersci. Conf. Antimicrob. Agents Chemother., abstracts 2153 and 2154, 2000). Data from the Urals and the southern part of Russia are preliminary and must be confirmed by testing more strains.

The prevalence of drug resistance in pneumococci and S. pyogenes throughout the cities in the Russian Federation studied is currently low. However, the apparent presence of a nidus of increased resistance in Siberia, as well as a multiresistant strain from Smolensk, indicates potential for the spread of these organisms in the future.

The prevalence of macrolide resistance among pneumococci was generally low in all of the regions of Russia studied (2.5%). However, rRNA and ribosomal protein mutations were significant mechanisms of macrolide resistance among these isolates (3 of 12). The prevalence of macrolide resistance was higher in S. pyogenes than in S. pneumoniae and was associated with four clones. Five strains from three distinct regions of Russia were found to belong to same clone.

In summary all pneumococci and 99.2% of S. pyogenes isolates, irrespective of their erythromycin resistance, were susceptible to telithromycin at a breakpoint of 0.5 µg/ml, as well as being uniformly susceptible to levofloxacin and quinupristin-dalfopristin. Telithromycin, therefore, has considerable potential for the empirical treatment for community-acquired infections caused by macrolide-susceptible and -resistant S. pneumoniae and S. pyogenes.

 
We are grateful to Lyubov Katosova, Natalya Furletova, and Elena Gugucidze (Moscow); Natalya Marusina (Kazan); Igor Smirnov (Ryazan); Vladimir Kuzin (Nizhnij Novgorod); Shamil Palyutin (Yaroslavl); Olga Kretchikova (Smolensk); Tatyana Shustrova and Galina Tseneva (St. Petersburg); Irina Multikh (Krasnodar); Lyudmila Ahmetova and Lyubov Boronina (Ekaterinburg); Irina Molchanova (Chelyabinsk); Lyubov Gudkova (Tomsk); Elena Agapova (Irkutsk); Eduard Ortenberg (Tyumen); and Vera Ilyina (Novosibirsk) for the bacterial strains used in the study.

This study was supported by a grant from Aventis.

 
* Corresponding author. Mailing address: Department of Pathology, Hershey Medical Center, Mail code H083, 500 University Dr., Hershey, PA 17033. Phone: (717) 531-3910. Fax: (717) 531-7953. E-mail: bozdogan-b{at}psu.edu.

Top Abstract Introduction Materials and Methods Results Discussion References

 

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Antimicrobial Agents and Chemotherapy, September 2002, p. 2963-2968, Vol. 46, No. 9
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.9.2963-2968.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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