key: cord-0036756-rehrja28
authors: Jalava, Jari; Seppälä, Helena
title: Antibiotic Resistance of Non-Pneumococcal Streptococci and Its Clinical Impact
date: 2009
journal: Antimicrobial Drug Resistance
DOI: 10.1007/978-1-60327-595-8_2
sha: 53b63b5b51b466f6041a42d7843e312055143962
doc_id: 36756
cord_uid: rehrja28

Viridans streptococci (VGS) form a phylogenetically heterogeneous group of species belonging to the genus Streptococcus (1). However, they have some common phenotypic properties. They are alfa- or non-haemolytic. They can be differentiated from S. pneumoniae by resistance to optochin and the lack of bile solubility (2). They can be differentiated from the Enterococcus species by their inability to grow in a medium containing 6.5% sodium chloride (2). Earlier, so-called nutritionally variant streptococci were included in the VGS but based on the molecular data they have now been removed to a new genus Abiotrophia (3) and are not included in the discussion below. VGS belong to the normal microbiota of the oral cavities and upper respiratory tracts of humans and animals. They can also be isolated from the female genital tract and all regions of the gastrointestinal tract (2, 3). Several species are included in VGS and are listed elsewhere (2, 3). Clinically the most important species belonging to the VGS are S. mitis, S. sanguis and S. oralis.

Viridans streptococci (VGS) form a phylogenetically heterogeneous group of species belonging to the genus Streptococcus (1) . However, they have some common phenotypic properties. They are alfa-or non-haemolytic. They can be differentiated from S. pneumoniae by resistance to optochin and the lack of bile solubility (2) . They can be differentiated from the Enterococcus species by their inability to grow in a medium containing 6.5% sodium chloride (2) . Earlier, so-called nutritionally variant streptococci were included in the VGS but based on the molecular data they have now been removed to a new genus Abiotrophia (3) and are not included in the discussion below. VGS belong to the normal microbiota of the oral cavities and upper respiratory tracts of humans and animals. They can also be isolated from the female genital tract and all regions of the gastrointestinal tract (2, 3) . Several species are included in VGS and are listed elsewhere (2, 3) . Clinically the most important species belonging to the VGS are S. mitis, S. sanguis and S. oralis.

Beta-hemolytic streptococci can be differentiated from the heterogeneous group of streptococci by the pattern of hemolysis on blood agar plates, antigenic composition, growth characteristics, biochemical reactions and genetic analyses. Beta-hemolytic streptococci commonly produce hemolysins, which cause complete lysis (beta-hemolysis) of red blood cells when cultivated on blood agar plates. Non-hemolytic strains can also be pathogenic. Traditional subdividing into serological groups is based on the detection of group-specifi c antigenic differences in cell wall carbohydrates using the serologic scheme of classifi cation by Lancefi eld (4) . Serogroups A, B, C, D, F and G are those most commonly found in humans (5).

Group A streptococcus (GAS, Streptococcus pyogenes) is an important pathogen confi ned almost exclusively to human hosts. Transmission occurs from persons with acute infections or from asymptomatic carriers usually through hand contact and respiratory droplets, but food-and waterborne outbreaks have also been documented (6) . GAS is a common cause of bacterial infections especially in children of more than 3 years of age, and also in other age groups. Most commonly the diseases are selflimiting, localized infections of the pharynx and skin (e.g. pharyngitis and impetigo). However, invasion especially from the skin can lead to septicaemia or severe deep-seated tissue infections, such as necrotizing fasciitis and myositis. Other clinical manifestations of GAS include scarlet fever, peritonsillar and retropharyngeal abscesses, otitis media, sinusitis, myositis, lymphangitis, meningitis, suppurative arthritis, endocarditis, osteomyelitis, pneumonia, erysipelas, cellulites, streptococcal toxic shock syndrome, vaginitis, and balanitis (7) (8) (9) (10) . Primary suppurative infections may also lead to serious nonsuppurative sequelae, acute rheumatic fever and acute glomerulonephritis (11, 12) .

Serologic typing of the M (13) and T proteins (14) has traditionally been used in epidemiologic typing of GAS (15) . Nowadays, molecular typing methods such as emm sequence typing, multilocus sequence typing, pulse fi eld gel electrophoresis, inversion gel electrophoresis, restriction length polymorphism analysis of the mga-regulon (vir-typing) and random amplifi ed polymorphic DNA analysis, have provided more discriminatory power for studying the clonal relationships between GAS strains.

Group B streptococci (GBS, Streptococcus agalactiae) is one of the primary causes of bacteremia and meningitis in neonates and infections in pregnant women (16, 17) . It is also an important cause of invasive infections in the elderly and in non-pregnant adults with underlying or chronic diseases. The clinical spectrum of invasive GBS disease in adults includes skin and soft tissue infections, primary bacteremia, urosepsis, pneumonia, osteomyelitis, peritonitis, septic arthritis, meningitis, endocarditis, and intravenous catheter infection. Vaginal colonization of non-pregnant and pregnant women is the principal source of GBS. GBS has been classifi ed into different serotypes on the basis of different chain structures of its capsular polysaccharide.

Most of the Lancefi eld group C streptococci (GCS) produce beta-haemolysis on blood agar although non-hemolytic strains also exist. GCS are mainly animal pathogens. Group C beta-hemolytic streptococci have been isolated from human normal microbiota of nasopharynx, skin and genital tract. Of the four group C streptococci species S. equisimilis is the most common human isolate (2) . Most of the group G streptococci (GGS) are beta-haemolytic. As GCS, they are also found in human normal microbiota of nasopharynx, skin and genital tract. Both GCS and GGS cause pharyngitis and a variety of severe infections in humans (2).

Penicillin and beta-lactam resistance in general, among streptococci is mediated by point mutations in the penicillinbinding proteins (PBPs). PBPs are membrane-bound trans-peptidases, active-site serine hydrolases, which catalyse cross-linking of the peptidoglycan subunits during the bacterial cell wall synthesis (18, 19) . Beta-lactam antibiotics serve as substrates for PBPs. The active-site serine reacts with the beta-lactam ring and generates a covalently linked enzymebeta-lactame intermediate. This acyl enzyme intermediate is not able to catalyse cross-linking of the peptidoglycan subunits (18) . In streptococci there are low-and high-molecularweight PBPs (20, 21) . Both of these enzymes are important for cell wall synthesis, but only the high-molecular-weight PBPs are important for the bacterial killing activity of the beta-lactam antibiotics (19) . In VGS there are two kind of high-molecular-weight PBPs: PBP1 (PBP1a and PBP1b) and PBP2 (PBP2a, PBP2b, PBP2x) (20) . Homologous molecules can be found from S. pneumoniae and naming conventions for PBPs of the VGS are adapted from S. pneumoniae (19) (20) (21) . VGS with wild-type PBSs are susceptible to beta-lactam antibiotics (22) . In order to become resistant, they have to decrease the affi nity of beta-lactams to the high-molecularweight PBPs. This can be achieved by amino acid substitutions in the transpeptidase domain of the PBPs (19, 22) . One point mutation can result in slight increase in the penicillin MIC. Normally more than one mutation is needed for intermediate-level beta-lactam resistance. Highly resistant strains have accumulated several mutations in the PBPs. Based on the data obtained from S. pneumoniae; these highly resistant strains may also need mutations other than PBP (19) . Accumulation of several mutations in the PBPs may also lead to lethal mutations. Streptococci have overcome this problem by horizontal transfer of functional mutated PBPcoding genes or gene fragments. Transformation and subsequent homologous recombination has produced beta-lactamresistant VGS with mosaic PBP genes. In these mosaics of PBP genes there are gene regions obtained from resistant strains dispersed through the wild-type PBP genes (23) .

Penicillin resistance among VGS isolated from blood has been extensively studied (Table 1 ). These results indicate that low-level penicillin resistance is quite a common character in blood isolates (up to 56%). However, highly resistant VGS strains can also be found, and the resistance rates vary between 2 and 24%. There are small differences in the resistance levels in different countries (Table 1 ). Only few reports are available of the resistance among VGS isolated from human normal microbiota (33, 35) . Penicillin resistance of these VGS strains is at the same level as among the strains isolated from blood samples (Table 1) .

VGS strains, that have increased MICs for penicillin, have typically decreased susceptibility to all beta-lactams including piperzillin, cephalosporins and carbapenems (24) . Of the third-generation cephalosporins, ceftriaxone is the most active against VGS in vitro (24) . The NCCLS resistance breakpoint for ceftriaxone was 2 mg/L until 2002 when it changed to 4 mg/L (43, 44) . Using the old breakpoint for ceftriaxone, penicillin and ceftriaxone resistance levels are similar (Table 1) . In different studies, resistance percentages of VGS for ceftriaxone vary between 0 and 27% ( Table 1) . As expected, cefotaxime is almost as active as ceftriaxone against VGS although there is not as much resistance data available (24, 34) . It is of worth to note that a third-generation cephalosporin, ceftazidime, although very active against various Gram-negative bacteria, is not as active as penicillin, cefotaxime or ceftriaxone against VGS (8, 12) . As presented in Table 1 , most of the blood isolates have a reduced susceptibility to ceftazidime with up to 70% resistance. Resistance levels of the fourth-generation cephalosporin, cefepime, vary between 11 and 42% (Table 1 ). However, the new NCCLS breakpoint for cefepime is 4 mg/L and if that is used the highest level of resistance is 19% (30) . Whatsoever, all this data indicate that penicillin is in vitro as effective as cephalosporins against VGS although ceftriaxone has, in vitro, lower resistance fi gures than penicillin if the new NCCLS breakpoints are used (43, 44) . Imipemen, a carbapenem antibiotic, is in vitro active against VGS (45) . Most of the VGS strains have low imipenem MIC values, i.e. less than 0.5 mg/L (24, 31) . However, strains, highly penicillin resistant, can have elevated MICs (1-2 mg/L) (24). Marron et al., have found that 20% of the VGS blood isolates of neutropenic cancer patients can have imipenem MIC of 1 mg/L or more (31) . Similarly, Diekema et al. reported that 11% of VGS strains had imipenem MICs equal to or higher than 0.5 mg/L (29) . The problem with imipenem is that there are no NCCLS breakpoints for non-pneumococcal streptococci (44) . Streptococci are in vitro highly susceptible to another carbapenem compound, meropenem. Only few resistant strains with MICs as high as 2 mg/L have been found (46).

Macrolides, ketolides, lincosamides and streptogramin B antibiotics, although having different kind of chemical structure, all have similar although not identical antimicrobial activity against VGS. The resistance mechanisms developed by bacteria against these antimicrobials are also similar. All these antibiotics inhibit protein synthesis by binding to bacterial ribosomes. Macrolides can be divided into different groups according to the number of carbon atoms in their lactone ring. 14-and 15-membered ring macrolides, like erythromycin and azithromycin, have similar antibacterial properties. Sixteen-membered ring macrolides, like spiramycin, differ from 14-and 15-membered ring macrolides in their antimicrobial activity against VGS. Also lincosamides ( clindamycin) and streptogramins have some differences in their activity against bacteria, when compared to macrolides. In streptococci, there are two well-characterised macrolide resistance mechanisms: target site modifi cation and active drug effl ux. Target site modifi cation is mediated by methylases encoded by the erm (erythromycin ribosome methylation) genes or by mutations at the 23S ribosomal RNA or ribosomal proteins L4 and L22. Methylation of adenine 2058 of the peptidyl transferase loop of 23S rRNA causes resistance to macrolides as well as to lincosamides and streptogramin B antibiotics (47) . The active effl ux mechanism, encoded by the mef (macrolide effl ux) genes, is more specifi c and causes resistance only to 14-and 15-membered-ring macrolides (48) . Mutations at the macrolide-binding domains of the 23S ribosomal RNA and at the ribosomal proteins L4 and L22 lower the affi nity of macrolides to ribosomes (39) . Mutations can cause several different kinds of resistance phenotypes. Both erm and mef genes can be horizontally transferred between different streptococci (49).

Erythromycin A has similar in vitro activity against VGS strains as other 14-and 15-membered ring macrolides including azithromycin (33) . The resistance against erythromycin is quite common among clinical VGS isolates. In the blood isolates, the resistance level is between 27 and 40% ( Table 2 ). The VGS strains isolated from normal microbiota ( Table 2) are also often resistant to erythromycin, the resistance levels being at the same level as among the blood isolates (33, 50, 53) . The most common erythromycin resistance mechanism is mediated by mef(A) genes (33, 53) . Roughly 70-80% of the erythromycin resistant VGS strains carry mef(A) gene and about 16-20% carry erm(B) gene (33, 38, 53) . However, the situation may vary. There is one report from France, where erm(B) gene was reported to be much more common than mef(A) gene among blood isolates of VGS (49).

Resistance against clindamycin is much less frequent among blood and normal microbiota VGS than resistance to erythromycin. Resistance fi gures vary between 2 and 10%. Resistance levels are similar among both blood and the normal microbiota isolates ( Table 2 ). The reason for lower resistance levels 

is that the effl ux mechanism mediated by mef(A) resistance gene, does not confer resistance to clindamycin(54).

Ketolides, represented here by telithromycin -the fi rst ketolide on the market, are new-generation macrolides, in which a 3-keto group replaces l-cladinose in the lactone ring. Ketolides have shown to be in vitro more active than macrolides against the erythromycin-resistant S. pneumoniae and S. pyogenes strains (55). NCCLS does not yet offer telithromycin breakpoint values for other streptococci than S. pneumoniae (44) . If the estimation of telithromycin resistance is done based on the breakpoint values of S. pneumoniae, telithromycin-resistant clinical VGS strains do not exist ( Table 2 ). The binding of telithromycin to the bacterial ribosomes is much stronger than the binding of the erythromycin. This is the reason why methylation of the ribosomal RNA does not increase the MIC values as much as it does for erythromycin (56) . Neither do the Mef(A) effl ux pumps transport telithromycin out of the bacterial cell as well as they pump erythromycin. However, in streptococci, Mef(A) effl ux does elevate telithromycin MIC when compared to the strains without mef(A) gene (55) . In every case, telithromycin seems to be the most active macrolide group antimicrobial on the market at the moment.

Quinupristin-dalfopristin (Synercid R ), a combination of streptogramin B and streptogramin A antibiotics, is available for intravenous use. It has rather good in vitro activity against VGS. However, resistance rates between different studies vary a lot (Table 3 ). In some studies, resistant strains have not been found at all, but in other studies 70% of the strains have showed reduced susceptibility and 28% have been resistant (26, 52) . Also VGS strains, which have quinupristin-dalfopristin MIC of 16 mg/L have been described (26) . Resistance against quinupristin-dalfopristin combination is linked to the streptogramin A (dalfopristin) resistance, so that in order to be resistant against the antibiotic combination, a strain must be resistant to streptogramin A. Streptogramin B resistance is not necessary. Streptogramin A resistance is mediated by vga(A), vga(B), lsa and various vat genes. Thus far, these genes have been found in clinical Staphylococcus and Enterococcus strains, but the presence of the genes in VGS has not been reported (57) .

Although not studied in detail (26, 37) , it is possible that the resistance is mediated by ribosomal mutation like in S. aureus (58).

Tetracycline resistance among VGS is quite common. 23-39% of the strains are tetracycline resistant (33, 41, 45, 53, 59) . Tetracycline resistance rates are similar as are the erythromycin resistance rates. Trimethoprim-sulfamethoxazole is not used for treatment of VGS infections but is commonly used for prophylaxis of neutropenic patients (60) . Reduced susceptibility against it is quite common among VGS strains ( Table 2 ).

In streptococci, there are two fl uoroquinolone resistance mechanisms: mutations at the quinolone resistance-determining regions (QRDRs) of the topoisomerase IV and DNA gyrase molecules, and an effl ux mechanism (61) (62) (63) . In streptococci, toposisomerase IV molecule has two subunits coded by parC and parE genes. The DNA gyrase has also two subunits GyrA and GyrB coded by corresponding genes. Topoisomerase IV is the primary target for fl uoroquinolones in VGS (61) . Mutations at the topoisomerase IV genes confer low-level resistance (MIC 4 mg/L). A combination of topoisomerase IV mutations and fl uoroquinolone effl ux mechanism is needed for high-level fl uoroquinolone resistance (MIC of 16 mg/L or more). Fluoroquinolone resistance determinants can be horizontally transferred between VGS and S. pneumoniae strains (61, (64) (65) (66) . New fl uoroquinolones levofl oxacin and moxcifl oxacin are active against Gram-positive bacteria. Levofl oxacin is active against both VGS strains of normal microbiota (33) and blood isolates (38, 41) . Only few levofl oxacin resistant strains have been found thus far (33, 38, 41) . NCCLS does not have interpretive standards for moxifl oxacin yet, and therefore resistance rates cannot be determined. However, the activity of the moxifl oxacin is somewhat better than that of levofl oxacin. MIC 90 values for moxifl oxacin and levofl oxacin are 0.25 mg/L and 0.5 mg/L, respectively (38) . In addition, all VGS strains studied for their in vitro susceptibility for moxcifl oxacin so far have had MIC of equal or less than 2 mg/L (33, 38) (Table 3 ). Ciprofl oxacin is less active than levofl oxacin or moxifl oxacin. About 8% of the VGS blood isolates are resistant to ciprofl oxacin (38).

Vancomycin, a glycopeptide antibiotic, has retained its activity against VGS. Not a single vancomycin-resistant VGS has been reported thus far (25, 27, 31-33, 40, 51, 59). MICs for vancomycin are typically between 0.125 and 1 mg/L (27, (30) (31) (32) 51) and MIC 90 values between 0.5 and 1 mg/L (27, 51) . Teicoplanin, another glycopeptide antibiotic, is also active against VGS, although there are no NCCLS breakpoints available for this antibiotic (44) . MIC 90 values for teicoplanin are 0.25 mg/L or less (25, 32, 40, 51) . In general, the activity of the aminoglycosides against VGS is limited (67). Aminoglycosides like gentamycin, amikacin, streptogramin and netilmicin, are used in combination with penicillin or a cephalosporin for the treatment infective endocarditis (68) and sepsis in neutropenic patients (69) . High-level gentamicin resistance (MIC of 500 mg/L or more) to VGS is very rare. This is true with VGS isolates of blood origin (25, 32, 40) as well as with VGS strains from the normal microbiota (35) . MIC values are typically between 0.25 and 96 mg/L (25, 32, 45) and the MIC 90 values between 0.5 and 32 mg/L (32, 35) . However, few high-level aminoglycosidesresistant S. mitis strains have been detected. In these strains gentamicin MICs have been as high as 1,000 mg/L (45).

Linezolid is an antibacterial agent belonging to the new oxazolidinone group of antibacterials. Oxazolidinones are not related to any other antibacterials in use (70) . Linezolid has been used in the treatment of vancomycin-resistant Enterococcus faecium infections, hospital-acquired pneumonia and complicated skin infections (71) . The activity of linezolid against VGS strains has not been studied well. However, in those few studies the in vitro activity of linezolid has been good. Only one VGS strain of the 298 strains studied have had linezolid MIC of 4 mg/L (38, 52).

In 1959 Lowburry and Hurst (72) reported the fi rst isolate of erythromycin-resistant GAS from burns of four patients in the United Kingdom. During the following years in Europe, mainly sporadic cases and small epidemics of erythromycin-resistant GAS were reported from the United Kingdom, Sweden, Italy and Spain (72) (73) (74) (75) (76) (77) . Also in the United States and Canada low proportions, 5% or less, were reported (78-80) except in a study with 22% of erythromycin-resistant GAS in Florida in 1980 (81) . In the 1970s the largest outbreak of erythromycin-resistant GAS occurred in Japan, where the proportion of resistant strains increased from 12% in 1971 to 82% in 1977 (82) . These strains were characterized as highly resistant (MICs > 100 mg/L) to macrolides and lincomycin and they were often resistant also to tetracycline and chloramphenicol and were exclusively of T12 serotype. In 1985-1987, an increase from 1 to 17.6% in the frequency of erythromycin-resistant GAS was seen in Australia Fremantle area (83) . These strains represented different serotypes and exhibited low-level resistance to erythromycin (MICs (2-8 mg/L) and resistance to clindamycin and tetracycline was rare. In 1988-1989 sporadic isolates and family outbreaks with 22% of erythromycin-resistant GAS was reported from the Dundee area in the United Kingdom with predominance of T4M4 serotype (84) . Thereafter, in 1990 a nationwide increase of erythromycin-resistant GAS of multiclonal origin was reported from Finland, where the frequencies reached 24%, 20% and 31% among blood culture, pharyngeal and pus isolates, respectively (75) . Since the beginning of 1990s increased frequencies has been reported from several countries. Today macrolide resistance in GAS is a worldwide problem. Increased fi gures include the following frequencies of macrolide- 

Resistance to erythromycin has been reported in GBS since 1962. The fi rst description was from the United States (112) and in the same country an increase in the rate of macrolide resistance in GBS from 1.2% among isolates collected in 1980-1993 to 18% in 1997-1998 was reported (113) . Increasing frequencies have been reported also from other countries. In Spain, the frequency of macrolide resistance in GBS increased from 2.5 to 5.6% in 1993-1996 to 14.5-18% in 1998-2001 (114) and in Taiwan from 19% in 1994 to 46% in 1997 (115) . Since the end of the 1990s frequencies of 15-21% have been reported in France (116) (117) (118) , 13-18% in Canada (119, 120) , 40% in Korea (121) and 22% in Turkey (122).

Macrolide resistance among group C and G streptococci varies a lot among different countries. In Finland resistance has not been very common. 3.6% and 1.0% of the GCS have been resistant to erythromycin and clindamycin, respectively. The most common macrolide resistance mechanism has been mef(A) (123) . Similarly 3.5% and 0.3% of the GGS have been resistant to erythromycin and clindamycin, respectively. Most of these strains have had erm(TR) resistance gene and only one have had erm(B) (123) . A bit higher numbers of erythromycin resistance among GCS and GGS have been reported from Turkey. Ergen et al. (23) reported that 1.4% and 16.2% of GCS and GGS were resistant to erytromycin respectively. In Taiwan, erythromycin resistance among GCS and GGS has been more common, 41.7% and 53.3% of the GCS and GGS isolates being erythromycin resistant (124).

The macrolide resistance mechanism by ribosomal methylation encoded my erm genes, which was fi rst identifi ed in 1956 in Staphylococcus aureus (125) , affects macrolides, linconamides and streptogramin B (MLSb) antibiotics. The inducible and constitutive forms of MLSb resistance has been found in beta-hemolytic streptococci since the early 1970s (126) (127) (128) . The erm(B) methylase gene was the only erm gene class found in streptococci (129-131) until 1998, when the sequence of erm(TR) in S. pyogenes was published (132) . Its nucleotide sequence is 82.5% identical to staphylococcal erm(A) and 58% identical to erm(B) and therefore erm(TR) belongs to erm(A) methylase gene class (133) . The inducible or constitutive production of the methylase is dependent on the sequence of the regulatory region situated upstream from the structural methylase gene. It has been shown that in clindamycin, highly resistant mutants of S. pyogenes harbouring inducible erm(TR) and originally susceptible to clindamycin could be selected by 0.12-1 mg/L concentrations of clindamycin. Resistance was associated to structural changes in the regulatory sequence (134) . The phenotypic expression of macrolide resistance in strepto-cocci has been commonly studied by MIC determinations and induction tests including the double-disk test (erythromycin and clindamycin disks placed in vicinity on inoculated agar). Analysis of the Finnish GAS strains isolated in 1990 indicated a new erythromycin resistance phenotype with low-or moderate-level resistance (MICs 1-32 mg/L) to 14-and 15-membered macrolides only (M-phenotype). Thirty-four percent of the studied isolates represented the new phenotype (76) . Subsequently, the active effl ux mechanism causing this phenotype and the encoding mef(A) and mef(E) (macrolide effl ux) genes were characterized in S. pyogenes and S. pneumoniae (48, 135, 136) and isolates with this mechanism have been found among beta-haemolytic streptococci in different parts of the world. Countries, where strains of GAS carrying mef(A) have been observed to account nowadays for the majority of macrolide-resistant isolates, include Spain (86, 137) , Germany (97) and Greece (93) , Finland (138), Taiwan (105), the United States (139), Chile (110) and Argentina (111) . Predomination of GAS strains carrying erm(A) have been reported from Russia, Slovakia, Czech Republic and Croatia (103, 140) . In GBS isolates with MLS resistance caused by erm(B) and ermA predominate in most reports in Canada and other parts of the Western Hemisphere (120, 141), France (116, 117, 142) , Spain (114, 143, 144) and Taiwan (115) . So far, GBS and GCS with the highest proportion of isolates carrying mef(A), 37% and 95%, have been reported from Taiwan and Finland, respectively (145, 146) . In addition to macrolide resistance determinants of erm(B), erm(A) and mef(A), all of which have been found from beta-haemolytic streptococci all over the world, a more rare mechanism, i.e. mutations in the S. pyogenes ribosomal protein L4 and in positions 2611 and 2058 of 23S rRNA encoding genes have been recently shown to cause resistance to macrolides. Mutations in positions 2611 and 2058 of the 23S rRNA gene cause resistance to clindamycin and streptogramin B (quinupristin), and also mutation at 2058 to telithromycin (147) (148) (149) . The presence of a putative novel effl ux system associated with erm(TR) in S. pyogenes has also recently been found (150) . Another gene, mreA, which was originally described as a macrolide effl ux gene in S. agalactiae (151) , is encoding ribofl avin kinase and is found also in erythromycin-susceptible GBS strains (152) . Strains with two different macrolide resistance mechanisms (mef and erm) within a single bacterial cell also exist among GAS and more commonly among GBS (86, 100, 116, 122, 143, 152, 153) . The phenotype of these strains is usually that determined by the erm gene.

While mef(A) and constitutively expressed erm(B) and erm(A) determinants provide constant and predictable phenotypes in beta-haemolytic streptococci, the phenotypes of inducible expressed erm(B) and especially erm(A) may vary. Isolates with mef(A) have low-or moderate-level resistance to 14-and 15-membered macrolides and isolates with either of the erm genes with constitutive expression have commonly high-level resistance to 14-, 15-and 16-membered macrolides, lincosamides and streptogramin B antibiotics. Inducible strains, especially those with erm(A) are often susceptible to 16-membered macrolides and clindamycin, but become highly resistant (MICs > 128 mg/L) to clindamycin and moderately or highly resistant to 16-membered macrolides after induction with subinhibitory concentrations of erythromycin. Also low-level resistance to ketolides can be induced (76, 153) . Beta-haemolytic streptococci with inducible erm(B) are more commonly associated to highlevel resistance to MLSb-antibiotics than isolates with inducible erm(A) gene (122, 153) . In epidemiological studies the distribution of the resistance mechanisms, the expression of erm(A) has more often been inducible and that of erm(B) has more often been constitutive in GAS, but among GBS constitutive erm(A) and inducible erm(B) are also rather common (122, 144) , e.g. in Turkey, isolates with inducible erm(B) accounted for majority of macrolide resistance in GBS (122) .

erm (B) has been shown to be either plasmid or chromosome borne in streptococci (133) . In earlier studies conjugative plasmids with the erythromycin resistance determinants were found from group A, B, C and G streptococci and they were shown to transfer by conjugation between streptococcal species (154) and among GAS also by transduction (155, 156) . However, most antibiotic resistance genes are nowadays thought to be chromosomal in streptococci, and betahaemolytic streptococci belonging to groups A, B, C and G have been shown to transfer their chromosomal macrolide resistance determinants by conjugation (152, (157) (158) (159) . A composite chromosomal conjugative element Tn3701, encoding resistance to erythromycin and tetracycline has been described in GAS (160) . Within this element the resistance genes are carried by a Tn916-like transposon. The presence of Tn916-Tn1545-like conjugative transposons carrying erm(B) and tet(M) has been verifi ed later in GAS in other studies (161, 162) and an association of chromosomal erm(A) with tet(O) has been noted in some strains of GAS (161) . An unusual chimeric genetic element containing DNA identical to Tn1207.1, a transposable element carrying mef(A) in macrolide-resistant S. pneumoniae, has also been found in different GAS strains. The mechanism of horizontal transfer in these strains was suggested to be transduction (163) . Furthermore, analysis of the genetic environments of the mef(A) and erm(B) genes by Southern blot experiments have indicated a remarkable heterogeneity of genetic elements carrying these genes, especially erm(B), suggesting that different mobile elements can be recruited into the chromosomes of the circulating GAS population and that genetic rearrangement may also occur after a strain has acquired the resistance determinant (162).

A large variety of clones of GAS are mediating macrolide resistance (105, 162, 164, 165) . Increased resistance rates may be caused by clonal spread of resistant strains and by horizontal transfer of resistance determinants among the circulating microbial population. Macrolide-resistant GAS of the same clone have been found from different countries and even different continents (164) and the same clones have been found among susceptible isolates, but in general the heterogeneity of GAS clones seems to be lower among resistant than susceptible isolates (162, 164, 165) . Single clones of GAS with a macrolide-resistant determinant may become regionally or nationally widely predominant or cause outbreaks (100, 108, 109, 166) . For example, in Finland, 82% of isolates of erythromycin-resistant GAS collected all over the country in 1994 expressed the M-phenotype; although multiple clones were found among these isolates, increased regional resistance rates were clearly associated to a clone of T4M4 serotype with mef(A) (138, 158) . In Taiwan, 33% of the erythromycin-resistant GAS collected in 1992-1995 and 1997-1998 carried constitutive erm(B) and were of one clonal origin. Sixty-four percent carried mef(A) of which only 23% were of one clonal origin and 16 other clones were found among the rest of these isolates (105) . In Russia, 87% of erythromycin-resistant GAS collected in 2000-2001 carried inducible erm(TR) and 86% of these were of one clonal origin (103) . In the United States, Pittsburgh, isolates carrying mef(A) of an emm6 (M6 serotype) clone that caused an epidemic among school children in 2001 were not at all found in the region within a two-month period in April-May in 2002, when the resistance rate was again at a high level (35% of isolates were resistant to erythromycin); this time an emm75 (M75 serotype) clone predominated (109, 139) . In Italy, Cresti et al. found that a steady increase of erythromycin-resistant GAS from 9% in 1992 to 53% in 1997 in an area in central Italy was caused by an increase of the proportion of strains carrying inducible and constitutive erm(B) and erm(TR) determinants. These strains were of multiclonal origin. Correlation of the erythromycin-resistant GAS clones to the heterogeneity of genetic elements carrying the erm(B) indicated identical genetic environments of erm(B) in clonally unrelated strains, but on the other hand also indicated considerable diversity of these genetic elements both among clonally unrelated and within clonally identical strains (162) . The increase of resistance, therefore, includes a complex genetic interaction within circulating streptococcal population and maybe between streptococci and other species (167) . Macrolide consumption and different immunity status and other host factors of populations are also possible factors that contribute to this interplay and spread of resistance determinants and resistant clones (168-170).

Clindamycin resistance is almost exquisitely related to MLS resistance in beta-haemolytic streptococci and is thus mediated by erm genes. However, in some studies among GBS the frequency of clindamycin resistance exceeds that of macrolide resistance suggesting another mechanism of clindamycin resistance (114, 121, 171) . In one isolate of GBS from Canada, the linB gene encoding a lincosamide-inactivating nucleotidyltransferase, was found (120) . This gene has previously been identifi ed in Enterococcus faecium.

Resistance to telitromycin is so far rare. Only a few strains, with such high MIC values for telithromycin that they can be considered as resistant, have been isolated. These isolates have constitutively expressed erm(B) gene or they have adenine-to-guanine mutation at the position 2058 (55, 149).

Resistance to tetracycline is common among beta-haemolytic streptococci, especially among macrolide resistant strains. As much as 80% of the beta-haemolytic streptococci in Korea, have been reported to be resistant to tetracycline (121) . However, only 16.1% and 0.5% of GAS isolated in Germany and Canada respectively, are shown to be resistant to tetracycline (97, 172) . Resistance is caused by tetracycline resistance to ribosomal protection proteins encoded by tet(M) or tet(O).

The tet(M) gene is the most widely distributed and is found in GAS often in linkage with erm(B) on mobile elements (161), but in GBS it is found both among macrolide-susceptible and macrolide-resistant organisms with all different macrolide resistance determinants (143) . Tet(O) has been found in GAS carrying chromosomal erm(A) or mef(A) and it can transfer with or without erm(A) and with mef(A) (161).

Infective endocarditis, despite proper treatment, is a lifethreatening condition (173) . The etiology of infective endocarditis varies according to the age of patients and the clinical nature of the disease (173) (174) (175) (176) . VGS cause about 28% of all cases (173, 176) . The proportion of VGS among native valve endocarditis varies between 11 and 43% (174, 177) , and VGS are the most common cause of late prosthetic-valve endocarditis (174, 175, 177) . Several different VGS species have been reported to cause endocarditis, S. sanguis (68, 174) , S. mitis, S. oralis and S. gordonii (177) being the most common species isolated from blood or infected valves. Among intravenous drug abusers, the VGS do not have as important a role as they have in general (174) . In the point of view of the treatment and prophylaxis, penicillin resistance is a cause of concern. The treatment recommendation for infective endocarditis caused by penicillin-susceptible (MIC ≤0.1 mg/L) streptococci is intravenous penicillin G for 4 weeks combined with intravenous gentamicin for 2 weeks (68, 178, 179) . Instead of penicillin, ceftriaxone also can be used in combination with gentamicin (68, 178) . Streptococcal strains with reduced susceptibility to penicillin (MIC > 0.1 mg/L) can be treated with penicillin G in combination with gentamicin. However, higher dose of penicillin and longer treatment times (4-6 weeks) are recommended (68, 178, 179) . Low-level penicillin resistance among VGS isolated either from blood samples or normal microbiota is quite common. From 17 up to 56% show penicillin MIC of 0.125 mg/L or higher (Table 1) . Although, there is not much data available in the literature, this low-level penicillin resistance seem not to be a significant clinical problem. Penicillin and aminoglycoside, most often penicillin and gentamicin, combination has synergistic activity against VGS (178) . In the literature there are a few documented cases where patients with endocarditis caused by intermediately penicillin-resistant streptococcus were treated successfully with penicillin-gentamicin or in one case a penicillin-streptomycin combination (180) . Also penicillin therapy alone followed by cephalotin and vancomycin therapies has been successfully used for treatment of endocarditis caused by low-level penicillin resistant streptococci (180) .

High-level penicillin resistance (MIC of 4 mg/L of more) rates among VGS vary between 2 and 24% ( Table 1) . Among VGS from endocarditis patients, high-level penicillin resistance is rare. Only a few strains with MICs higher than or equal to 4 mg/L, have been reported (40, (179) (180) (181) (182) (183) . Decreased susceptibility among VGS strains from normal microbiota is common. In the future, penicillin nonsusceptible streptococci will more often cause endocarditis infections, and it is also likely that high-level penicillin resistance will increase. This is a challenge because optimal treatment regimens have not yet been determined in endocarditis caused by highly penicillin-resistant VGS. Thus far, all VGS strains tested have been susceptible to vancomycin (68, 178) . There are reports where vancomycin alone (182) and vancomycin, ceftriaxone and gentamicin in combination (183) has been successfully used for treatment of endocarditis caused by highly resistant streptococci. However, some reports show that treatment of endocarditis caused by highly penicillin-resistant streptococci can be diffi cult. In one study, neither vancomycin treatment alone, nor a cefotaxime-gentamicin combination, was enough to completely cure endocarditis caused by a highly penicillin-resistant S. mitis strain in a human immunodefi ciency virus positive individual (181) . Also the vancomycin-gentamicin combination failed to cure endocarditis caused by highly penicillin-resistant S. sanguis in a 65-year-old woman with multiple medical problems (180) . This indicates that other antibiotic regimens may be needed. Possible new candidates are levofl oxacin, moxifl oxacin, quinupristin/dalfopristin and linezolid. Resistance against these antibiotics is rare. However, the usage of these agents may select resistant strains especially among streptococci in the normal microbiota. For example, point mutations causing resistance to quinupristin/dalfopristin combination have already been described in other bacterial species (58) . The same is true with fl uoroquinolones, where point mutations are able to cause low-level resistance among streptococci (38, 61, 64) . Linezolid-resistant strains are very rare, although one strain with linezolid resistance (MIC 4 mg/L) has been reported (38) . Oxazolinones are bacteriostatic antibiotics and in that sense their usage for treatment of infective endocarditis may be compromised (70) . However, linezolid has been successfully used for treatments of endocarditis caused by vancomycin-resistant enterococci and methicillin-resistant staphylococci (71, 184) . At the moment there is no information of the effi cacy of linezolid in the treatment of endocarditis caused by VGS.

Increasing numbers of penicillin-resistant VGS strains among normal microbiota may also challenge the prevention therapies of infective endocarditis. Amoxicillin or ampicillin is recommended for endocarditis prophylaxis (68) . The prophylactic use of these antibiotics may select penicillinresistant VGS strains among normal microbiota and these strains may be able to cause infective endocarditis (181) . Clindamycin, which is recommended for prophylaxis for patients allergic to penicillin (68) , might be, from the point of view of resistance, a better choice at the moment (Table 2) . However, use of macrolides can also select clindamycinresistant strains among normal microbiota streptococci, because Erm(B) methylase is able to cause both macrolide and clindamycin resistance. So, it is possible that in the future the clindamycin resistance rates are also higher than now. Telithromycin is very active against VGS strains of normal microbiota. erm(B) and mef(A) resistance genes do not mediate telithromycin resistance among VGS (33) , although the presence of mef(A) gene in streptococci is increasing the MIC values (55) . So, just from the resistance point of view, prophylactic use of telithromycin might be a better choice than the use of clindamycin.

Infections are an important cause of morbidity and mortality among neutropenic patients, although the mortality caused by infections has signifi cantly decreased during recent years (185, 186) . There have been changes in the aetiology of bacteremia in febrile neutropenic patients. Earlier, Gram-negative bacteria were the most common cause. Nowadays, up to 70% of the bacteremia in neutropenic patients is caused by Grampositive bacteria (185) (186) (187) (188) . Possible reasons for this shift in the aetiology are the use of antibiotic prophylaxis, increased use of intravenous catheters and aggressive chemotherapies with prolonged neutropenia and mucositis (186, 187, 189, 190) . VGS are an important cause of bacteremia among neutropenic patients. Depending on the study the proportion of VGS as a cause of bacteremia ranges between 3 and 30% (31, 187, 188, (191) (192) (193) . S. mitis followed by S. oralis or S. sanguis are the most commonly isolated species (24, 188, (193) (194) (195) . Bacteremias caused by VGS strains originate from the oral mucosa (42, 196) . Predisposing factors for VGS infections are severe and prolonged neutropenia, prophylactic antibiotic treatments with quinolones or trimethoprim-sulfamethoxazole, mucositis and treatment of chemotherapyinduced gastritis with antacids or histamine type 2 antagonists (189, 195) . VGS infections can be associated with a high morbidity and mortality. Range of overall mortality of VGS bacteremia is between 6 and 18%, but this does not differ from the mortality rate of bacteremia caused by other bacteria (185, 194, 197) . VGS infections can be rather asymptomatic, fever being the most common symptom (189, 194, (197) (198) (199) . 4 to 26% of the patients with VGS infections develop serious complications, like septic shock, acute respiratory distress syndrome (ARDS) or both (31, 189, 194, 197, 198) . Mortality among patients that develop ARDS is high, up to 60-100% (31, 189, 194) . Adequate empirical antimicrobial therapy of neutropenic patients with fever is essential, because infection may progress rapidly. The empirical therapy should cover both Grampositive and Gram-negative bacteria (200) (201) (202) . Especially important is that empirical treatment cover VGS and Pseudomonas aeruginosa strains (201) . Recommendation for empirical therapy depend on the risk of the of neutropenic patients to develop serious complication during the febrile episode (200) . Empiric antibacterial treatment for low-risk neutropenic patients relies on ciprofl oxacin or levofl oxacin with or without amoxicillin-clavulanate (200) (201) (202) . In addition, fl uoroquinolones with clindamycin has been suggested (200) . Monotherapy with new fl uoroquinolones, which show better activity against Gram-positive bacteria is not yet suggested for empirical treatment of low-risk neutropenic patients (200) . Empirical antibacterial treatment of high-risk neutropenic patient relies on broad-spectrum parenteral antibiotics. Third-(ceftazidime) or fourth-(cefepime) generation cephalosporin alone or together with an aminoglycoside, or carbapenem either alone or in combination with aminoglycoside are the fi rst choice of drugs (201, 202) . Also, piperacillin-tazobactam either alone or in combination with aminoglycoside is recommended (185) . Glycopeptides should be avoided in order to reduce the development of glycopeptide-resistant bacterial strains (185) . It has also shown that empirical addition of vancomycin to the therapy would not give any benefi t, when compared to piperacillin-tazobactam therapy (203) .

Antimicrobial resistance of streptococci isolated from neutropenic patients have been widely studied. These studies indicate that low-level penicillin resistance is common. 21 to 39% of the VGS strains isolated from neutropenic patients present reduced susceptibility against penicillin (28, 30, 36, 42, 51) . However, as much as 57% of the VGS strains have been reported to be non-susceptible to penicillin (204) . Highly resistant VGS strains (MIC≥4 mg/L) can also be found, the resistance rates varying typically between 2 and 24% (30, 36, 42, 51) . Penicillin and especially highly penicillin resistant VGS strains are often resistant to cephalosporins and also express reduced susceptibility to imipenem (30) . In these cases ceftazidime is not active (29, 30) . Despite the high rates of penicillin resistance among VGS strains, penicillin resistance has not been associated with the development of severe complications, like ARDS (30, 31, 189) or the overall mortality (30) . However, there are few reports, which indicate that increasing rates of penicillin resistance might cause problems in the empirical treatment of neutropenic patients with VGS bacteremia. For example, Marron et al. (30) reported a breakthrough bacteraemia of ceftazidime-resistant VGS strains among patients receiving ceftazidime treatment. Similarly, Elting et al. (188) reported that neutropenic patients with VGS infections who did not receive vancomycin in the initial empiric therapy, died more often than-patients who received initial vancomycin therapy. Also in the same study it was shown that patients with penicillin-susceptible VGS infections responded to the initial therapy better than patients with penicillin-resistant VGS, although the fi nal outcome was not affected by penicillin resistance (188) .

Carbapenems are active against VGS in vitro (46) and are recommended for empirical treatment of neutropenic patients (200) (201) (202) . However, VGS strains with elevated (1-2 mg/L) MICs for carbapenems have been isolated from neutropenic patients (24, 29, 30) . Whether resistance among VGS strains will in the future compromise the use of carbapenems for monotherapy of neutropenic patients will be seen.

Glycopeptides, linezolid and quinupristin/dalfopristin are not used alone for empirical treatment of febrile neutropenic patients because of their low activity against Gram-negative bacteria. However, glycopeptides are in vitro very effective against VGS and are widely used as a combination with other antibacterials (203) . Linezolid has been shown to be as effective as teicoplanin for treatment of Gram-positive infections (205, 206) . The same is true with quinupristin/dalfopristin (207) . However, there is lack of data as to how well these new drugs are suited for treatment of streptococcal infections. At the moment they are not recommended for empirical therapy of febrile neutropenic patients (200) .

The combined use of both fl uoroquinolones and penicillin as prophylaxis for bacterial infections in neutropenic patients has reduced bacteremic, especially streptococcal, episodes (199, 208, 209) . However, this kind of prophylaxis does not reduce the overall morbidity or mortality. Penicillin resistance among VGS strains may affect the effi ciency of penicillin prophylaxis. Whether this will affect the morbidity or mortality of neutropenic patients will be seen.

The importance of identifying antimicrobial resistance in beta-hemolytic streptococci is dependent upon whether these antimicrobials are used for treatment and whether the in vitro resistance leads to clinical treatment failure. Penicillin is the drug of choice for treatment of streptococcal infections and macrolides are considered as an alternative treatment for penicillin-allergic patients. In the treatment of pharyngitis caused by GAS, it has been shown that the eradication rate is lower (38-60%) when 14-and 15-membered macrolides are used against macrolide-resistant strains in comparison to the eradication rate (80-92%) when these agents are used against macrolide-susceptible organisms (99, 210, 211) . The use of a macrolides for the treatment of macrolide-resistant GAS pharyngitis is also associated with a signifi cantly lower clinical cure rate compared to that achieved with amoxicillin, amoxicillin-clavulanate or cefaclor (211) . In addition, it has been shown that regardless of the macrolide resistance mechanism and of epidemiological origin, the erythromycin-resistant isolates harbour the prtF1 gene, more often, encoding a protein that enhances the ability to enter respiratory cells, than erythromycin-susceptible organisms (212) . Macrolideresistant GAS strains are so far mostly susceptible to telithromycin, which is a better choice than macrolides. However, few resistant strains exist and the knowledge of resistance and resistance mechanisms is important. The same is true with clindamycin. Use of clindamycin against an erythromycin-resistant isolate requires knowledge of the result of both the susceptibity testing and the determination of the macrolide resistance phenotype for a given isolate, because clindamycin should not be used against isolates with the MLSb-phenotype (134) . Since we lack many alternatives for macrolides, and beta-hemolytic streptococci, especially GAS and GBS, may cause serious infections and non-suppurative sequelae, limiting the use of macrolides should be encouraged (213, 214) . The selective pressure caused by the amount of macrolides used in the community has been shown to correlate to the level of macrolide resistance in GAS in the community (168) (169) (170) 215) and reduction of use of these agents has been shown to lead to reduction of macrolide resistance (213, 214) .

Because GBS is the leading cause of neonatal infections, intrapartum antibiotic prophylaxis is recommended for colonized women with increased risk factors, such as low gestational age. For those at risk, intrapartum penicillin therapy is recommended, with ampicilin, clindamycin, erythromycin and vancomycin as acceptable alternative treatments (CDC), with penicillin G being the drug of choice (216) .

There has been debate of the remarkable state of susceptibility to penicillin in GAS and other beta-hemolytic streptococci and of the probability of this state to continue. Resistance to penicillin occurs in related species, such as S. pneumoniae, VGS and enterococci. Among the reasons for the continuing susceptibility to penicillin in GAS, the following have been suggested: the pathogens ineffi cient mechanisms for genetic transfer or barriers to DNA uptake and replication and the fi ndings that low-affi nity PBPs expressed by penicillin-resistant laboratory mutants of GAS have a potentially defective performance in the cell-wall biosynthesis, thus decreasing the viability of the penicillin-resistant organism (28, 217) .

Determination of 16S rRNA sequences of Streptococcus mitis and Streptococcus gordonii and phylogenetic relationships among members of the genus Streptococcus

Viridans streptococci and groups C and G streptococci

Current classification of the oral streptococci

A serological differentiation of human and other groups of hemolytic streptococci

Classification of streptococci

Direct inoculation of food as the cause of an outbreak of group A streptococcal pharyngitis

Streptococcus pyogenes vulvovaginitis in children in Nottingham

Streptococcal infections of skin and soft tissues

Balanitis caused by group A beta-hemolytic streptococci

Streptococcus pyogenes

Variation in group A streptococci and the prevalence of rheumatic fever: a half-century vigil

Does antimicrobial therapy of streptococcal pharyngitis or pyoderma alter the risk of glomerulonephritis?

Current knowledge of type-specific M antigens of group A streptococci

The serological classification of Streptococcus pyogenes

The use of the serum opacity reaction in the typing of group-A streptococci

Identification of streptococci to species level by sequencing the gene encoding the manganese-dependent superoxide dismutate

Streptococcus agalactiae (group B streptococcus)

Antibiotics: Actions, Origins, Resistance

Penicillin-binding protein-mediated resistance in pneumococci and staphylococci

Genome sequence of Streptococcus mutans UA159, a cariogenic dental pathogen

Genome of the bacterium Streptococcus pneumoniae Strain R6

Penicillin-resistant viridans streptococci have obtained altered penicillin-binding protein genes from penicillin-resistant strains of Streptococcus pneumoniae

In vitro susceptibility, tolerance and MLS resistance phenotypes of Group C and Group G streptococci isolated in Turkey between 1995 and 2002

In vitro activities of 22 β-lactam antibiotics against penicillin-resistant and penicillin-susceptible viridans group streptococci isolated from blood

Antimicrobial susceptibility of 278 streptococcal blood isolates to seven antimicrobial agents

Emergence of high rates of antimicrobial resistance among viridans group streptococci in the United States

Nosocomial streptococcal blood stream infections in the SCOPE program: species occurrence and antimicrobial resistance

Antimicrobial resistance in viridans group streptococci among patients with and without the diagnosis of cancer in the USA, Canada and Latin America

Comparison of activities of broad-spectrum beta-lactam compounds against 1,128 gram-positive cocci recently isolated in cancer treatment centers

High rates of resistance to cephalosporins among viridans-group streptococci causing bacteraemia in neutropenic cancer patients

Serious complications of bacteremia caused by viridans streptococci in neutropenic patients with cancer

Antimicrobial susceptibility of viridans group streptococci in Taiwan with an emphasis on the high rates of resistance to penicillin and macrolides in Streptococcus oralis

Antimicrobial susceptibility patterns and macrolide resistance genes of viridans group streptococci from normal flora

Nosocomial bloodstream infections due to viridans streptococci in haematological and non-haematological patients: species distribution and antimicrobial resistance

Antibiotic resistance rates and macrolide resistance phenotypes of viridans group streptococci from the oropharynx of healthy Greek children

In vitro activities of the New Ketolide HMR 3647 (Telithromycin) in comparison with those of eight other antibiotics against viridans group streptococci isolated from blood of neutropenic patients with cancer

In vitro activities of eight macrolide antibiotics and RP-59500 (quinupristin-dalfopristin) against viridans group streptococci isolated from blood of neutropenic cancer patients

Activities of new fluoroquinolones, ketolides, and other antimicrobials against blood culture isolates of viridans group streptococci from across Canada

Ribosomal mutations in Streptococcus pneumoniae clinical isolates

Antibiotic susceptibility of streptococci and related genera causing endocarditis: analysis of UK reference laboratory referrals

In vitro activities of fluoroquinolones against antibiotic-resistant blood culture isolates of viridans group streptococci from across Canada

Molecular relationships and antimicrobial susceptibilities of viridans group streptococci isolated from blood of neutropenic cancer patients

Performance Standards for Antimicrobial Susceptibility Testing

Performance Standards for Antimicrobial Susceptibility Testing; Fourteenth Informational Supplement

In vitro antimicrobial susceptibility of viridans streptococci isolated from blood cultures

MYSTIC (meropenem yearly susceptibility test information collection) results from the Americas: resistance implications in the treatment of serious infections

Erythromycin resistance by ribosome modification

Streptococcus pneumoniae and Streptococcus pyogenes resistant to macrolides but sensitive to clindamycin: a common resistance pattern mediated by an efflux system

Incidence of mefA and mefE genes in viridans group streptococci

Susceptibilities of oral and nasal isolates of Streptococcus mitis and Streptococcus oralis to macrolides and PCR detection of resistance genes

& The Multicenter Study on Antibiotic Resistance in Staphylococci and Other Gram-Positive Cocci (Mars) Study Group (2001) Nationwide German multicenter study on the prevalence of antibiotic resistance in streptococcal blood isolates from neutropenic patients and comparative in vitro activities of quinupristin-dalfopristin and eight other antibiotics

Daptomycin in vitro susceptibility in European Gram-positive clinical isolates

Prevalence and characterization of the mechanisms of macrolide, lincosamide and streptogramin resistance in viridans group streptococci

Mechanisms of resistance to macrolides and lincosamides: nature of the resistance elements and their clinical implications

In vitro activities of the novel ketolide telithromycin (HMR 3647) against erythromycin-resistant Streptococcus species

Activity of the ketolide telithromycin is refractory to Erm monomethylation of bacterial rRNA

Occurrence and epidemiology of resistance to virginiamycin and streptogramins

Resistance to quinupristin-dalfopristin due to mutation of L22 ribosomal protein in Staphylococcus aureus

High prevalence of erythromycin-resistant and clindamycin-susceptible (M phenotype) viridans group streptococci from pharyngeal samples: a reservoir of mef genes in commensal bacteria

Ofloxacin versus trimethoprimsulfamethoxazole for prevention of infection in patients with acute leukemia and granulocytopenia

Drug efflux and parC mutations are involved in fuoroquinolone resistance in viridans group streptococci

Fluoroquinolone resistance mutations in the parC, parE, and gyrA genes of clinical isolates of viridans group streptococci

Fluoroquinolone resistance associated with target mutations and active efflux in oropharyngeal colonizing isolates of viridans group streptococci

Horizontal transfer of parC and gyrA in fluoroquinoloneresistant clinical isolates of Streptococcus pneumoniae

Viridans group streptococci are donors in horizontal transfer of topoisomerase IV genes to Streptococcus pneumoniae

In vitro exchange of fluoroquinolone resistance determinants between Streptococcus pneumoniae and viridans streptococci and genomic organization of the parE-parC region in S. mitis

Aminoglycosides and aminocyclitols

Guidelines on prevention, diagnosis and treatment of infective endocarditis executive summary

Piperacillin-tazobactam plus amikacin versus ceftazidime plus amikacin as empiric therapy for fever in granulocytopenic patients with cancer

Quinupristin-dalfopristin and linezolid: evidence and opinion

Linezolid for the treatment of multidrug-resistant, gram-positive infections: experience from a compassionate-use program

The sensitivity of staphylococci and other wound bacteria to erythromycin, oleandomycin, and spiramycin

Group A streptococci resistant to clindamycin

Antibiotic susceptibility of group A streptococci: a 6-year follow-up study

Resistance to erythromycin in group A streptococci

Three different phenotypes of erythromycin-resistant Streptococcus pyogenes in Finland

Streptococcus pyogenes; erythromycin resistance and molecular typing

Resistance of group A beta-hemolytic streptococci to lincomycin and erythromycin

Susceptibility of group A beta-hemolytic Streptococcus isolates to penicillin and erythromycin

Erythromycin-resistant group A beta-hemolytic streptococci: prevalence at four medical centers

Antibiotic-resistant streptococci

Drug resistance in Streptococcus pyogenes strains isolated in Japan

The emergence of erythromycin resistance in Streptococcus pyogenes in Fremantle, Western Australia

Erythromycin-resistant Streptococcus pyogenes

Antimicrobial susceptibilities of 1,684 Streptococcus pneumoniae and 2,039 Streptococcus pyogenes isolates and their ecological relationships: results of a 1-year (1998-1999) multicenter surveillance study in Spain

Macrolide resistance phenotypes and mechanisms of resistance in Streptococcus pyogenes in La Rioja

Significant increase in the prevalence of erythromycin-resistant, clindamycin-and miocamycin-susceptible (M phenotype) Streptococcus pyogenes in Spain

Antibiotic resistance rates and macrolide resistance phenotypes of viridans group streptococci from the oropharynx of healthy Greek children

Emergence of group A beta-hemolytic streptococci resistant to erythromycin in Athens, Greece. Eur

Erythromycin resistance amongst group A beta-haemolytic streptococci isolated in a paediatric hos

High prevalence of erythromycin resistance of Streptococcus pyogenes in Greek children

In vitro activity of telithromycin (HMR 3647) against Greek Streptococcus pyogenes and Streptococcus pneumoniae clinical isolates with different macrolide susceptibilities

Clinical isolates of macrolide-resistant Streptococcus pyogenes in Central Greece

Antimicrobial resistance in Streptococcus pyogenes isolates in Berlin

Macrolide resistance in Streptococcus pyogenes isolates from throat infections in the region of Aachen

Macrolide-resistant Streptococcus pneumoniae and Streptococcus pyogenes in the pediatric population in Germany during

Phenotypes of macrolide resistance of group A streptococci isolated from outpatients in Bavaria and susceptibility to 16 antibiotics

Macrolide resistance in group A streptococci

Nationwide survey in Italy of treatment of Streptococcus pyogenes pharyngitis in children: influence of macrolide resistance on clinical and microbiological outcomes. Artemis-Italy Study Group

Resistance to macrolides in Streptococcus pyogenes in France in pediatric patients

Genetic and phenotypic characterization of macrolide resistance in group A streptococci isolated from adults with pharyngo-tonsillitis in France

Development of macrolide resistance by ribosomal protein L4 mutation in Streptococcus pyogenes during miocamycin treatment of an eight-year-old Greek child with tonsillopharyngitis

Antistreptococcal activity of telithromycin compared with seven other drugs in relation to macrolide resistance mechanisms in Russia

Increased prevalence of erythromycin resistance in streptococci: substantial upsurge in erythromycinresistant M phenotype in Streptococcus pyogenes (1979-1998) but not in Streptococcus pneumoniae (1985-1999) in Taiwan

Prevalence of polyclonal mefA-containing isolates among erythromycin-resistant group A streptococci in Southern Taiwan

The emergence of erythromycin-resistant Streptococcus pyogenes in Seoul

Macrolide resistance and distribution of erm and mef genes among betahaemolytic streptococci in Hong Kong

Emergence of macrolide resistance in throat culture isolates of group a streptococci in Ontario, Canada

Erythromycin-resistant group S streptococci in schoolchildren in Pittsburgh

Prevalence and mechanisms of macrolide resistance in Streptococcus

Genetic and phenotypic characterization of resistance to macrolides in Streptococcus pyogenes from Argentina

Neonatal sepsis and other infections due to group B betahemolytic streptococci

Change in antibiotic resistance of group B streptococcus: impact on intrapartum management

Erythromycin and clindamycin resistance and telithromycin susceptibility in Streptococcus agalactiae

High incidence of erythromycin resistance among clinical isolates of Streptococcus agalactiae in Taiwan

Antibiotic susceptibility and mechanisms of erythromycin resistance in clinical isolates of Streptococcus agalactiae: French multicenter study

Mechanisms of macrolide resistance in clinical group B streptococci isolated in France

Genetic basis of antibiotic resistance in Streptococcus agalactiae strains isolated in a French hospital

Group B streptococci causing neonatal bloodstream infection: antimicrobial susceptibility and serotyping results from SENTRY centers in the Western Hemisphere

Prevalence and mechanisms of macrolide resistance in invasive and noninvasive group B streptococcus isolates from Ontario

Emerging erythromycin resistance among group B streptococci in Korea

Macrolide resistance determinants of invasive and noninvasive group B streptococci in a Turkish hospital

Different erythromycin resistance mechanisms in group C and group G streptococci

High incidence of erythromycin-resistant streptococci in Taiwan

Antagonisme in vitro entre l'erythromycine et la spiramycine

Inducible and constitutive resistance to macrolide antibiotics and lincomycin in clinically isolated strains of Streptococcus pyogenes

Infections with beta-hemolytic Streptococcus resistant to lincomycin and erythromycin and observations on zonal-pattern resistance to lincomycin

Conjugative R plasmids in Streptococcus agalactiae (group B). Plasmid

Deoxyribonucleic acid sequence common to staphylococcal and streptococcal plasmids which specify erythromycin resistance

A complex attenuator regulates inducible resistance to macrolides, lincosamides, and streptogramin type B antibiotics in Streptococcus sanguis

Complete nucleotide sequence of macrolide-lincosamide-streptogramin B-resistance transposon Tn917 in Streptococcus faecalis

A novel erythromycin resistance methylase gene (ermTR) in Streptococcus pyogenes

Nomenclature for macrolide and macrolide-lincosamide-streptogramin B resistance determinants

In vitro selection of resistance to clindamycin related to alterations in the attenuator of the erm(TR) gene of Streptococcus pyogenes UCN1 inducibly resistant to erythromycin

Molecular cloning and functional analysis of a novel macrolide-resistance determinant, mefA, from Streptococcus pyogenes

Molecular cloning and functional analysis of a novel macrolide-resistant determinant, mefA, from Streptococcus pyogenes

Comparative in vitro activities of linezolid, quinupristin-dalfopristin, moxifloxacin, and trovafloxacin against erythromycin-susceptible and -resistant streptococci

Clonal spread of group A streptococcus with the new type of erythromycin resistance. Finnish Study Group for Antimicrobial Resistance

Reemergence of macrolide resistance in pharyngeal isolates of group a streptococci in southwestern Pennsylvania

Macrolide resistance in streptococci and Haemophilus influenzae

Molecular epidemiology of macrolide resistance in neonatal bloodstream isolates of group B streptococci

Characterization of the Tn916-like transposon Tn3872 in a strain of abiotrophia defectiva (Streptococcus defectivus) causing sequential episodes of endocarditis in a child

Macrolide and tetracycline resistance and molecular relationships of clinical strains of Streptococcus agalactiae

In vitro activities of tigecycline against erythromycin-resistant Streptococcus pyogenes and Streptococcus agalactiae: mechanisms of macrolide and tetracycline resistance

High incidence of erythromycin-resistant streptococci in Taiwan

Different erythromycin resistance mechanisms in group C and group G streptococci

Emergence of group A streptococcus strains with different mechanisms of macrolide resistance

Resistance to macrolides in clinical isolates of Streptococcus pyogenes due to ribosomal mutations

Mutation at the position 2058 of the 23S rRNA as a cause of macrolide resistance in Streptococcus pyogenes

A novel efflux system in inducibly erythromycin-resistant strains of Streptococcus pyogenes

Molecular cloning and functional analysis of a novel macrolide-resistance determinant, mefA, from Streptococcus pyogenes

MLS resistance phenotypes and mechanisms in betahaemolytic group B, C and G streptococcus isolates in

Phenotypes and genotypes of erythromycin-resistant Streptococcus pyogenes strains in Italy and heterogeneity of inducibly resistant strains

Broad host range of streptococcal macrolide resistance plasmids

Transfer of a plasmid mediating antibiotic resistance between strains of Streptococcus pyogenes in mixed cultures

Bacteriophage P13234 mo-mediated intra-and intergroup transduction of antibiotic resistance among streptococci

Variability of chromosomal genetic elements in streptococci

Erythromycin resistance genes in group A streptococci in Finland. The Finnish Study Group for antimicrobial resistance

Conjugative transfer of the erm(A) gene from erythromycin-resistant Streptococcus pyogenes to macrolide-susceptible S. pyogenes, Enterococcus faecalis and Listeria innocua

Molecular analysis of a composite chromosomal conjugative element (Tn3701) of Streptococcus pyogenes

Presence of the tet(O) gene in erythromycinand tetracycline-resistant strains of Streptococcus pyogenes and linkage with either the mef(A) or the erm(A) gene

Resistance determinants and clonal diversity in group A streptococci collected during a period of increasing macrolide resistance

Structure and distribution of an unusual chimeric genetic element encoding macrolide resistance in phylogenetically diverse clones of group A streptococcus

Clonal relationships among isolates of erythromycin-resistant Streptococcus pyogenes of different geographical origin

Clonal relatedness of erythromycin-resistant Streptococcus pyogenes isolates in Germany

Clonal differences among erythromycinresistant Streptococcus pyogenes in Spain

Macrolide resistance in Peptostreptococcus spp. mediated by ermTR: possible source of macrolide-lincosamide-streptogramin B resistance in Streptococcus pyogenes

Streptococcus pyogenes resistance to erythromycin in relation to macrolide consumption in Spain

Outpatient use of erythromycin: link to increased erythromycin resistance in group A streptococci

Effect of macrolide consumption on erythromycin resistance in Streptococcus pyogenes in Finland in

Serotyping and antimicrobial susceptibility of group B streptococcus over an eight-year period in southern Taiwan

Prevalence and mechanisms of macrolide resistance in clinical isolates of group A streptococci from Ontario

Epidemiologic aspects of infective endocarditis in an urban population. A 5-year prospective study

Infective endocarditis at a large community teaching hospital, 1980-1990. A review of 210 episodes

Infective endocarditis in adults

Infective endocarditis: a diagnostic and therapeutic challenge for the new millennium. Scand

New developments in the treatment of infective endocarditis infective cardiovasculitis

New guidelines for the antibiotic treatment of streptococcal, enterococcal and staphylococcal endocarditis

Endocarditis caused by penicillin-resistant viridans streptococci: 2 cases and controversies in therapy

Endocarditis due to Streptococcus mitis with high-level resistance to penicillin and cefotaxime

Prosthetic-valve endocarditis caused by penicillin-resistant Streptococcus mitis

Endocarditis due to Streptococcus mitis with high-level resistance to penicillin and ceftriaxone

Isolated pulmonic valve infective endocarditis: a persistent challenge

Science and pragmatism in the treatment and prevention of neutropenic infection

Evolution, incidence, and susceptibility of bacterial bloodstream isolates from 519 bone marrow transplant patients

Changes in the etiology of bacteremia in febrile neutropenic patients and the susceptibilities of the currently isolated pathogens

Outcomes of bacteremia in patients with cancer and neutropenia: observations from two decades of epidemiological and clinical trials

Septicemia and shock syndrome due to viridans streptococci: a case-control study of predisposing factors

Management of the febrile neutropenic patient: a consensus conference

Microbiological data for patients with febrile neutropenia

Prospective study of 288 episodes of bacteremia in neutropenic cancer patients in a single institution

Bacteremia due to viridans streptococci in neutropenic patients: a review

The clinical spectrum of infections with viridans streptococci in bone marrow transplant patients

Bacteremia due to viridans streptococcus in neutropenic patients with cancer: clinical spectrum and risk factors

Viridans streptococcal bacteraemia in patients with neutropenia

Streptococcal bacteremia in adult patients with leukemia undergoing aggressive chemotherapy. A review of 55 Cases

Viridans streptococcal shock in bone marrow transplantation patients

Reduction of fever and streptococcal bacteremia in granulocytopenic patients with cancer

The infectious diseases society of America 2002 guidelines for the use of antimicrobial agents in patients with cancer and neutropenia: salient features and comments

Evidence-based recommendations for antimicrobial use in febrile neutropenia in Japan: executive summary

Initial empirical antimicrobial therapy: duration and subsequent modifications

Vancomycin versus placebo for treating persistent fever in patients with neutropenic cancer receiving piperacillin-tazobactam monotherapy

Bacteremia due to viridans streptococci that are highly resistant to penicillin: increase among neutropenic patients with cancer

Linezolid versus teicoplanin in the treatment of Gram-positive infections in the critically ill: a randomized, double-blind, multicentre study

Linezolid compared with teicoplanin for the treatment of suspected or proven Gram-positive infections

Role of quinupristin/dalfopristin in the treatment of Gram-positive nosocomial infections in haematological or oncological patients

Prophylaxis with fluoroquinolones for bacterial infections in neutropenic patients: a meta-analysis

Respiratory failure elicited by streptococcal septicaemia in patients treated with cytosine arabinoside, and its prevention by penicillin

Bacteriological and clinical efficacy of various antibiotics used in the treatment of streptococcal pharyngitis in Italy. An epidemiological study

Erythromycin resistance in Streptococcus pyogenes in Italy

Association between erythromycin resistance and ability to enter human respiratory cells in group A streptococci

& Finnish Study Group for Antimicrobial Resistance (1997) The effect of changes in the consumption of macrolide antibiotics on erythromycin resistance in group A streptococci in Finland

Decline of erythromycin resistance of group A streptococci in Japan

The relationship between trends in macrolide use and resistance to macrolides of common respiratory pathogens

Revised guidelines for prevention of earlyonset group B streptococcal (GBS) infection

Why have group A streptococci remained susceptible to penicillin? Report on a symposium

Ketolides-telithromycin, an example of a new class of antibacterial agents