In vitro susceptibility of viridans group streptococci ...

Scandinavian Journal of Infectious Diseases, 2007; 39: 508 513

ORIGINAL ARTICLE

In vitro susceptibility of viridans group streptococci isolated from blood in southwest Finland in 1993 2004

Scand J Infect Dis Downloaded from informahealthcare.com by Turku University on 06/30/14 For personal use only.

MARIANNE LINDGREN1, JARI JALAVA1, KAISU RANTAKOKKO-JALAVA2 & OLLI MEURMAN2 From the 1Department of Bacterial and Inflammatory Diseases, National Public Health Institute, Turku, and 2Department of Clinical Microbiology, Turku University Central Hospital, Turku, Finland

Abstract We studied in vitro activity against invasive viridans group streptococci (VGS) of penicillin and 4 newer antibiotics, i.e. telithromycin, linezolid, levofloxacin and quinupristin-dalfopristin. Also 7 other antibiotics were tested. Antibiotic susceptibility of 263 VGS blood isolates, collected from southwest Finland during a 12-y period was determined. We wished to discover whether there is an increasing trend of antimicrobial resistance among VGS in Finland. Our results showed that penicillin is still a good choice for treating VGS infections based on the considerably low resistance percentage, 2.3%. Also newer antibiotics showed good in vitro activity: susceptibilities for telithromycin, linezolid and levofloxacin were 100%, 98.9% and 94.6%, respectively. However, quinupristin-dalfopristin was not as effective as described in previous studies, with only 57% susceptibility.

Introduction Viridans group streptococci (VGS) are a diverse group of streptococci that are part of the normal human microbiota in upper respiratory tract, oral cavity, female genital tract and all sections of the gastrointestinal tract [1]. Viridans group streptococci have long been considered as minor pathogenic agents although they are the leading cause of subacute bacterial endocarditis. More recently, VGS have also emerged as important pathogens causing bacteraemia and sepsis in neutropenic cancer patients [2]. In the past VGS were considered to be uniformly susceptible to b-lactams, macrolides and tetracyclines. However, recent studies have shown that VGS are becoming increasingly resistant to many antibiotics. Also, VGS are considered to be a possible reservoir for the dissemination of macrolide resistance genes to the above pathogenic streptococcal species [3]. In addition, antimicrobial resistance is not homogeneous among the group [4,5]. The emergence of multiresistant isolates has also complicated treatment of infections caused by VGS, and therefore there is a need for new effective antibiotics

against them [6]. Already there are some protein synthesis inhibitors such as quinupristin-dalfopristin [2,7], linezolid [2,8 10] and telithromycin [11], which have shown good in vitro activity against VGS. The purpose of this study was to evaluate the activity of penicillin (PEN), the most commonly used antibiotic in VGS infections, and 4 new antibiotics quinupristin-dalfopristin (Q-D), telithromycin (TEL), linezolid (LZD) and levofloxacin (LVX) against invasive viridans group streptococci in Finland. Furthermore, 7 other antimicrobials (erythromycin (ERY), ceftazidime (CAZ), cefotaxime (CTZ), ceftriaxone (CRO), tetracycline (TET), gentamicin (GEN) and ciprofloxacin (CIP)) were tested. Materials and methods Bacterial strains A total of 263 VGS isolated from blood samples in Turku University Central Hospital between March 1993 and November 2004 were tested. Samples were first cultured in BACTEC aerobial and anaerobial

Correspondence: M. Lindgren, Human Microbial Ecology Laboratory, National Public Health Institute, Kiinamyllynkatu 13, FIN-20520 Turku, Finland. Tel: /358 2 3316631. Fax: /358 2 3316699. E-mail: [email protected]

(Received 7 September 2006; accepted 20 November 2006) ISSN 0036-5548 print/ISSN 1651-1980 online # 2007 Taylor & Francis DOI: 10.1080/00365540601131950

In vitro susceptibility of Finnish VGS blood culture bottles or in paediatric bottles (Becton Dickinson, Franklin Lakes, NJ USA) using BD BACTEC 9240 blood culture automate (Becton Dickinson). The bottles flagged as positive were subcultured onto blood, chocolate and fastidious anaerobe agar plates. Isolates were stored at /708C. For the present study VGS isolates were subcultured onto blood agar plates, either directly or through brain-heart infusion broth, and incubated for 20 24 h at 358C in a 5% CO2 atmosphere.


Susceptibility testing Minimum inhibitory concentrations (MIC) were determined by the agar dilution method, according to the protocols of the Clinical and Laboratory Standards Institute (CLSI) [12], using Mu¨ller-Hinton II agar (Becton Dickinson Microbiology Systems, Cockeysville, MD, USA) supplemented with 5% sheep blood. The following antibiotics were tested: penicillin G, ceftazidime, cefotaxime, ceftriaxone, erythromycin, tetracycline and gentamicin from Sigma-Aldrich Co (St. Louis, MO, USA); ciprofloxacin from Fluka (Buchs SG, Switzerland); levofloxacin, telithromycin and quinupristin-dalfopristin (30:70 ratio) from Aventis Pharma Ltd. (Kent, UK), and linezolid from Pharmacia & Upjohn Inc. (Kalamazoo, MI, USA). Results were read after incubation at 358C for 20 24 h, in ambient air. MICs were interpreted using CLSI criteria for Streptococcus spp. other than S. pneumoniae when available [12]. CLSI has no telithromycin, ciprofloxacin, gentamicin or ceftazidime breakpoints for VGS. For telithromycin we used breakpoints given for S. pneumoniae, whereas for ciprofloxacin, ceftazidime and gentamicin only MIC50 and MIC90 values were determined. S. pneumoniae ATCC 49619 was used as a control organism. Levofloxacin and linezolid resistance, tested primarily with the agar dilution method, was confirmed by E-test (AB Biodisk, Solna, Sweden) according to the manufacturer’s instructions. Decreased susceptibility to linezolid was also checked with disk diffusion test on Mu¨ller-Hinton II agar (agar thickness 4 mm) (Becton Dickinson Microbiology Systems). The inoculum level used was 0.5 McFarland and the plates were incubated at 358C for approximately 18 h with the linezolid discs (antibiotic content 30 mg) (Oxoid Ltd., Basingstoke, Hampshire, England). Results were interpreted using CLSI guidelines for Streptococcus spp. other than S. pneumoniae [12]. Furthermore, telithromycin susceptibility of 10 highly erythromycin resistant (MIC ]/128) strains was retested with the disk diffusion method to enhance detection of possible heteroresistance [13]. Telithromycin discs (antibiotic

509

content 15 mg) (Oxoid Ltd.) were used and results were interpreted using CLSI guidelines for Streptococcus pneumoniae [12].

Species identification and detection of macrolide resistance mechanisms The strains were originally identified using colony morphology, haemolysis and API 20 Strep test (bioMe´rieux, Marcy l’E´toile, France). 18 isolates that were resistant to levofloxacin, linezolid, quinupristin-dalfopristin or highly resistant to penicillin (MIC ]/4 mg/ml), were taken into more specific examination, and they were identified with an API 20 STREP V6.0 or a Rapid ID 32 STREP V2.0 (bioMe´rieux) and with the pyrosequencing method (Biotage Ab, Uppsala, Sweden). Species identification with pyrosequencing was based on heterogeneity in streptococcal 16S rRNA signature sequences and was performed as described previously [14]. Highly erythromycin-resistant isolates (n / 10) were investigated for the presence of the macrolide resistance genes mef (A/E), erm (B) and erm (TR) by the multiplex method [15] with the primers and PCR conditions described previously [16]. Results and discussion A total of 263 VGS isolates were tested against 12 different antimicrobial agents. In this study, we were particularly interested in comparing the in vitro activity of 4 new antibiotics (telithromycin, linezolid, levofloxacin and quinupristin-dalfopristin) to penicillin, which is the most used antimicrobial agent in VGS infections. A summary of the in vitro activities of tested antimicrobial agents performed with the agar dilution method is shown in Table I. Susceptibility order for VGS, based on the agar dilution test, was: TEL/LZD /CRO /CTX /LVX /PEN /ERY / TET /Q-D. All the VGS isolates were susceptible to telithromycin, but 13 isolates resistant to levofloxacin, linezolid or highly resistant to penicillin were found. In addition, 29 isolates were resistant to quinupristin-dalfopristin. We compared the in vitro activity of these 12 antibiotics in 3 different periods: 1993 1996 (period I), 1997 2000 (period II) and 2001 2004 (period III). Resistance percentages of different antibiotics in those 3 periods are presented in Figure 1. The highest rates of penicillin resistance among VGS have been detected in Europe (from 8% to 59.3%); however, in Finland reported rates have been lower (5%) [46,17 21]. In our VGS material the overall penicillin susceptibility was 85.0%. Of the 39 penicillin-non-susceptible isolates, 33 (12.7%)

510

M. Lindgren et al.

Table I. In vitro activities of different antibiotics against VGS, tested with agar dilution method. viridans group streptococci (263)

Penicillin a Ceftazidime b Cefotaxime a Ceftriaxone a Erythromycin a Tetracycline a Ciprofloxacin b Levofloxacin a Quinupristin-Dalfopristin Linezolid a Telithromycin c Gentamicin b a b c

a

MIC50 (mg/ml)

MIC90 (mg/ml)

MIC range %

Resistant %

Susceptible %

0.063 2 0.125 0.125 0.063 0.5 1 1 1 1 0.016 4

0.5 8 0.5 0.5 2 32 4 2 4 2 0.063 16

0.016 32 0.125 64 0.125 64 0.125 32 0.063 256 0.25 64 0.25 64 0.25 32 0.016 8 0.125 4 0.008 0.25 0.5 32

2.3 1.9 2.3 17.5 24.3 1.9 11.0 1.1

85.0 95.4 96.9 80.6 74.1 94.6 57.0 98.9 100.0

S and R interpreted using CLSI criteria for Streptococcus spp. other than S. pneumoniae. Only MIC50 and MIC90 values determined. S and R interpreted using CLSI criteria for S. pneumoniae.

showed intermediate resistance and 6 (2.3%) were highly resistant. Based on pyrosequencing (and, except for 1 strain, on biochemical profile also) those 6 highly penicillin resistant strains belonged to the S. mitis group (Table II), which is in accordance with previous observations that high-level penicillin resistance is most abundant among S. mitis isolates [4,22]. One of the penicillin resistant S. mitis strains was also resistant to levofloxacin. The first penicillin resistant isolates in our material were found during period II in 1997. In this period penicillin resistance was 5.7% and decreased to 0.8% in period III. There was also a correlation between cephalosporin and penicillin resistance [5,23]. Three of 6 highly penicillin resistant strains (MIC ]/4 mg/ml) were resistant to cefotaxime and ceftriaxone whereas only 1 out of 221 (0.45%) of the penicillin susceptible isolates was resistant to those cephalosporins.

Telithromycin was the most active of the tested antimicrobial agents according to MICs [6]. All of the tested VGS isolates were susceptible to telithromycin (MIC 0.008 0.25 mg/ml). Erythromycin resistance is rather common among VGS isolates [2,24]. However, in our study material only 17.5% of the VGS were resistant (MIC 1 256 mg/ml) to erythromycin, which is even lower than in the previous Finnish study (27%) [5]. Erythromycin resistance was highest (20.0%) in period I and decreased slightly later. Of the 10 highly (MIC ]/ 128 mg/ml) erythromycin resistant isolates, those 8 with erythromycin MIC /256 mg/ml had erm (B) gene, whereas no macrolide resistance determinant was found in isolates whose MICs were 128 or 256 mg/ml. As described previously [13], heterogeneous resistance to telithromycin has been detected in S. pneumoniae among erythromycin resistant

30 1993- 1996

25

1997- 2000 % of isolates


Antimicrobial agent

20

2001- 2004

15 10 5 0 PEN

CTX

CRO

ERY

TET

LVX

Q-D

LZD

TEL

Figure 1. Variation of antibiotic resistance in 3 different periods: Period I /1993 1996, period II /1997 2000 and period III/2001 2004. (PEN: penicillin,;CTX: cefotaxime; CRO: ceftriaxone; ERY: erythromycin; TET: tetracycline; LVX: levofloxacin; Q-D: quinupristindalfopristin; LZD: linezolid; TEL: telithromycin)

In vitro susceptibility of Finnish VGS

511

Table II. Species identification of resistant VGS, performed with pyrosequencing and API Strep-test.


Isolate no. 3027 3376 5224 5360 7720 4015 4856 7443 2359 2413 3002 4387 8197 352 2129 2790 6202 7864

Y

Resistance

MIC mg/ml

1998 1999 2001 2001 2004 1999 2000 2003 1997 1997 1998 2000 2004 1993 1996 1998 2002 2004

LVX/PEN LVX LVX LVX LVX LZD LZD LZD PEN PEN PEN PEN PEN Q-D Q-D Q-D Q-D Q-D

8/4 16 32 16 16 4 4 4 32 32 4 4 4 4 4 4 4 4

16S sequencing

API Strep

S.mitis S.mitis S.sanguinis/S.salivarius/S.mitisa S.sanguinis/S.salivarius/S.mitisa S.mitis S.anginosus S.anginosus S.anginosus S.mitis S.mitis S.mitis S.mitis S.mitis S.mitis S.bovis S.mitis S.sanguinis S.bovis

S.oralis b S.oralis b S.oralis b S. oralis b S. mitis c S.salivarius c S.constellatus S.constellatus S.mitis c S.mitis c S.bovis c S.mitis c S.mitis c S.oralis c S.bovis c S.oralis c S.sanguis c S.bovis c

Comment

c c

d

doubtful profile doubtful profile very good identification very good identification acceptable identification low discrimination very good identification good identification very good identification acceptable identification acceptable identification doubtful profile Good identification good identification excellent identification good identification good identification low discrimination

a

16S sequencing did not give any definite previously known streptococcal sequence. rapid ID 32 Strep V2.0. c API 20 Strep V6.0. d Verbal explanation of apiweb identification results. b

strains. According to the disk diffusion test, 1 of the highly erythromycin resistant isolates (MIC 256 mg/ml) had telithromycin disc zone diameter of 16.5 mm, which indicates intermediate resistance to telithromycin in S. pneumoniae [12]. However, no heteroresistance was detected. All the other isolates were susceptible to telithromycin (disc zone 22 30.5 mm), which was already proven with the agar dilution method. Tetracycline resistance was noted in 24.3%, and quinupristin-dalfopristin resistance in 11.0%, of the VGS isolates. Strains resistant to erythromycin are likely to exhibit cross-resistance to several antimicrobial agents, and, for example, tetracycline resistance genes are often found in the same mobile unit as erythromycin resistance genes [2,25]. In our material, of the 212 erythromycin susceptible strains, 18.9% were resistant to tetracycline and 9.4% to quinupristin-dalfopristin, whereas 50% of the 46 erythromycin resistant strains were resistant to tetracycline and 19.6% to quinupristin-dalfopristin. Resistance to linezolid is known to be very rare among Streptococcus species [2,9] and in our material linezolid was the second most effective of the tested antibiotics. Based on the agar dilution test, performed twice, 3 isolates were non-susceptible (MIC /4 mg/ml) to linezolid. These strains, isolated in 1999, 2000 and 2003 were identified as S. anginosus according to 16S rRNA pyrosequencing results (Table II), and they were not resistant to any other of the tested antibiotics. Linezolid susceptibility

was retested with E-test and the disk diffusion method. According to E-test results (MIC values 11.5 mg/ml) and results from the disk diffusion method (zone range 26 33 mm) those strains were, however, susceptible to linezolid. There is no certain explanation for higher linezolid MIC values in the agar dilution method. However, possible instability of linezolid could have influence on active concentrations in agar. In contrast to previous studies [20,26,27] quinupristin-dalfopristin was the most ineffective of the new antimicrobial agents; only 57% of the VGS isolates were susceptible to Q-D. Even if Q-D susceptibility percentage was low, only 29 isolates (11%) were resistant to Q-D, whereas the amount of intermediate resistant (MIC /2 mg/ml) isolates was remarkably high (31.9%). Resistance to Q-D increased from period I (6.5%) to period III (13.0%). Of the 29 Q-D resistant isolates 5 were identified with the pyrosequencing method. Results revealed that 2 of the VGS were S. bovis isolates, 2 S. mitis isolates and 1 S. sanguinis isolate, API 20 Strep V6.0 giving concordant identifications (Table II). There is no explanation for the reasonably high Q-D resistance percentage; however, similar resistance results have been reported in Taiwan [28]. MIC values of Q-D for S. pneumoniae ATCC 49619 strain were 0.5 1 mg/ml, performed 15 times, and were within the limits given by CLSI [12]. The susceptibility rate for levofloxacin was 94.6%. Since levofloxacin resistant VGS strains have already been detected in Europe [19], we


512

M. Lindgren et al.

expected to find levofloxacin resistant isolates also in our VGS material. The first such isolate was found in 1998, 1 y after levofloxacin gained a selling permit in Finland. Levofloxacin resistance rate in period II was 2.3%, and resistance stayed at the same level also in the third period. In this study, the total levofloxacin non-susceptibility was 5.4%. Intermediate levofloxacin resistance (MIC 4 mg/ml) was noted in 9 isolates, and high-level resistance (MIC 8 32 mg/ml) in 5 isolates. Resistance percentage (1.9%) was higher than in the previous Finnish study [5]. 16S rRNA sequencing identified 3 of the levofloxacin resistant strains as S. mitis, but the remaining 2 did not give any previously known streptococcal 16S sequence (Table II). Based on API Strep-test both of the isolates were identified as S. oralis, and also the 3 others belonged to the mitis group. Levofloxacin susceptibility of the 5 highly resistant isolates was confirmed by E-test to range between 12 and 32 mg/ml. Our results, levofloxacin resistance rate 1.9%, MIC90 value /2 mg/ml, and ciprofloxacin MIC90 value /4 mg/ml, confirmed the previous observation regarding VGS that levofloxacin is more active than the earlier quinolones, such as ciprofloxacin [1]. In this study we wished to discover whether there is an increasing trend of antimicrobial resistance among VGS in Finland, and whether there are any differences in resistance rates between newer and commonly used antibiotics. Our MIC results confirmed the previous observations [1,26] that the new antibiotics such as telithromycin and linezolid have proved very effective against invasive VGS, whereas quinupristin-dalfopristin was not as effective. However, decreased susceptibility of quinupristin-dalfopristin has previously been reported [28]. The new fluoroquinolone levofloxacin was evidently more effective than ciprofloxacin. To our delight, commonly used antibiotic penicillin showed better in vitro activity against VGS than in some other studies [5,24,29], and the erythromycin resistance rate was lower than previously reported [6,30]. 16S pyrosequencing was an effective method for species identification, and sequencing results correlated well with commercial biochemical tests. Results from API 20 Strep V6.0 and rapid ID 32 Strep V2.0 were in accordance with 16S signature sequences of different streptococci groups, although there were some differences in species level. In conclusion, in vitro activities of the different antimicrobial agents towards VGS in our material showed the same kind of efficacy that has been reported before in similar studies and no trends of increasing resistance were observed over the 12-y study.

Acknowledgements We thank Anna-Liisa Lumiaho for skilful technical assistance and Sanofi Aventis for providing telithromycin. This work was supported by an EVO grant of the hospital district of southwest Finland.

References [1] Gordon KA, Beach ML, Biedenbach DJ, Jones RN, Rhomberg PR, Mutnick AH. Antimicrobial susceptibility patterns of beta-haemolytic and viridans group streptococci: report from the SENTRY Antimicrobial Surveillance Program (1997 2000). Diagn Microbiol Infect Dis 2002;43: 157 62. [2] Rodriguez-Avial I, Rodriguez-Avial C, Culebras E, Picazo JJ. Distribution of tetracycline resistance genes tet(M), tet(O), tet(L) and tet(K) in blood isolates of viridans group streptococci harbouring erm(B) and mef(A) genes. Susceptibility to quinupristin/dalfopristin and linezolid. Int J Antimicrob Agents 2003;21:536 41. [3] Ioannidou S, Papaparaskevas J, Tassios PT, Foustoukou M, Legakis NJ, Vatopoulos AC. Prevalence and characterization of the mechanisms of macrolide, lincosamide and streptogramin resistance in viridans group streptococci. Int J Antimicrob Agents 2003;22:626 9. [4] Rodriguez-Avial I, Rodriguez-Avial C, Culebras E, Picazo JJ. In vitro activity of telithromycin against viridans group streptococci and Streptococcus bovis isolated from blood: antimicrobial susceptibility patterns in different groups of species. Antimicrob Agents Chemother 2005;49:820 3. [5] Lyytikainen O, Rautio M, Carlson P, Anttila VJ, Vuento R, Sarkkinen H, et al. Nosocomial bloodstream infections due to viridans streptococci in haematological and non-haematological patients: species distribution and antimicrobial resistance. J Antimicrob Chemother 2004;53:631 4. [6] Alcaide F, Benitez MA, Carratala J, Gudiol F, Linares J, Martin R. In vitro activities of the new ketolide HMR 3647 (telithromycin) in comparison with those of 8 other antibiotics against viridans group streptococci isolated from blood of neutropenic patients with cancer. Antimicrob Agents Chemother 2001;45:624 6. [7] Livermore DM. Quinupristin/dalfopristin and linezolid: where, when, which and whether to use? J Antimicrob Chemother 2000;46:347 50. [8] Cercenado E, Garcia-Garrote F, Bouza E. In vitro activity of linezolid against multiply resistant Gram-positive clinical isolates. J Antimicrob Chemother 2001;47:77 81. [9] Mutnick AH, Enne V, Jones RN. Linezolid resistance since 2001: SENTRY Antimicrobial Surveillance Programme. Ann Pharmacother 2003;37:769 74. [10] Swaney SM, Aoki H, Ganoza MC, Shinabarger DL. The oxazolidinone linezolid inhibits initiation of protein synthesis in bacteria. Antimicrob Agents Chemother 1998;42: 3251 5. [11] Lonks JR, Goldmann DA. Telithromycin: a ketolide antibiotic for treatment of respiratory tract infections. Clin Infect Dis 2005;40:1657 64. [12] CLSI, Performance Standards for Antimicrobial Susceptibility testing; fifteenth Informational Supplement M100S15. Vol. 24. 2005, Wayne, PA, USA: Clinical and Laboratory Standards Institute. [13] Rantala M, Haanpera-Heikkinen M, Lindgren M, Seppala H, Huovinen P, Jalava J. Streptococcus pneumoniae isolates resistant to telithromycin. Antimicrob Agents Chemother 2006;50:1855 8. /

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

513

In vitro susceptibility of Finnish VGS [14] Seppala H, Haanpera M, Al-Juhaish M, Jarvinen H, Jalava J, Huovinen P. Antimicrobial susceptibility patterns and macrolide resistance genes of viridans group streptococci from normal flora. J Antimicrob Chemother 2003;52:636 44. [15] Figueira-Coelho J, Ramirez M, Salgado MJ, Melo-Cristino J. Streptococcus agalactiae in a large Portuguese teaching hospital: antimicrobial susceptibility, serotype distribution, and clonal analysis of macrolide-resistant isolates. Microb Drug Resist 2004;10:31 6. [16] Rantala M, Huikko S, Huovinen P, Jalava J. Prevalence and molecular genetics of macrolide resistance among Streptococcus pneumoniae isolates collected in Finland in 2002. Antimicrob Agents Chemother 2005;49:4180 4. [17] Alcaide F, Linares J, Pallares R, Carratala J, Benitez MA, Gudiol F, et al. In vitro activities of 22 beta-lactam antibiotics against penicillin-resistant and penicillin-susceptible viridans group streptococci isolated from blood. Antimicrob Agents Chemother 1995;39:2243 7. [18] Ardanuy C, Tubau F, Linares J, Dominguez MA, Pallares R, Martin R. Distribution of subclasses mefA and mefE of the mefA gene among clinical isolates of macrolide-resistant (M-phenotype) Streptococcus pneumoniae, viridans group streptococci, and Streptococcus pyogenes. Antimicrob Agents Chemother 2005;49:827 9. [19] Jones RN, Pfaller MA. Potencies of newer fluoroquinolones against viridans group streptococci isolated in 637 cases of bloodstream infection in the SENTRY Antimicrobial Surveillance Programme (1997 to 1999): beyond Canada! Antimicrob Agents Chemother 2000;44:2922 3. [20] Kennedy HF, Gemmell CG, Bagg J, Gibson BE, Michie JR. Antimicrobial susceptibility of blood culture isolates of viridans streptococci: relationship to a change in empirical antibiotic therapy in febrile neutropenia. J Antimicrob Chemother 2001;47:693 6. [21] Marron A, Carratala J, Alcaide F, Fernandez-Sevilla A, Gudiol F. High rates of resistance to cephalosporins among viridans-group streptococci causing bacteraemia in neutropenic cancer patients. J Antimicrob Chemother 2001;47: 87 91. /

/

/


/

/

/

/

/

/

/

/

/

/

/

/

/

[22] Han XY, Kamana M, Rolston KV. Viridans streptococci isolated by culture from blood of cancer patients: clinical and microbiological analysis of 50 cases. J Clin Microbiol 2006; 44:160 5. [23] Uh Y, Shin DH, Jang IH, Hwang GY, Lee MK, Yoon KJ, et. al. Antimicrobial susceptibility patterns and macrolide resistance genes of viridans group streptococci from blood cultures in Korea. J Antimicrob Chemother 2004;53:1095 7. [24] Diekema DJ, Beach ML, Pfaller MA, Jones RN. Antimicrobial resistance in viridans group streptococci among patients with and without the diagnosis of cancer in the USA, Canada and Latin America. Clin Microbiol Infect 2001;7: 152 7. [25] Kataja J, Huovinen P, Skurnik M, Seppala H. Erythromycin resistance genes in group A streptococci in Finland. The Finnish Study Group for Antimicrobial Resistance. Antimicrob Agents Chemother 1999;43:48 52. [26] Anderegg TR, Biedenbach DJ, Jones RN. In vitro evaluation of AZD2563, a new oxazolidinone, tested against betahaemolytic and viridans group streptococci. J Antimicrob Chemother 2002;49:1019 21. [27] Tuohy M, Washington JA. Antimicrobial susceptibility of viridans group streptococci. Diagn Microbiol Infect Dis 1997;29:277 80. [28] Luh KT, Hsueh PR, Teng LJ, Pan HJ, Chen YC, Lu JJ, et al. Quinupristin-dalfopristin resistance among Gram-positive bacteria in Taiwan. Antimicrob Agents Chemother 2000; 44:3374 80. [29] Ergin A, Ercis S, Hascelik G. Macrolide resistance mechanisms and in vitro susceptibility patterns of viridans group streptococci isolated from blood cultures. J Antimicrob Chemother 2006;57:139 41. [30] Gershon AS, de Azavedo JC, McGeer A, Ostrowska KI, Church D, Hoban DJ, et al. Activities of new fluoroquinolones, ketolides, and other antimicrobials against blood culture isolates of viridans group streptococci from across Canada, 2000. Antimicrob Agents Chemother 2002;46: 1553 6. /

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/

/