In vitro activity of ketolides telithromycin and HMR 3004 against italian isolates of Streptococcus pyogenes and Streptococcus pneumoniae with different erythromycin susceptibility

Two ketolides, telithromycin and HMR 3004, were evaluated for their in vitro activity against erythromycin-susceptible and -resistant strains of Streptococcus pyogenes and Streptococcus pneumoniae. On the basis of their resistance to macrolide, lincosamide and streptogramin (MLS) antibiotics, erythromycin-resistant test strains were assigned to the constitutive resistance (cMLS) phenotype, the inducible resistance (iMLS) phenotype or the M phenotype. iMLS S. pyogenes strains were further subdivided into the three recently described subtypes iMLS-A, -B and -C. Telithromycin and HMR 3004 were uniformly and highly active against pneumococci (regardless of their susceptibility or resistance to erythromycin and/or penicillin), erythromycin-susceptible S. pyogenes and erythromycin-resistant S. pyogenes strains of the M phenotype (in which resistance is mediated by an efflux system) or iMLS-B or -C phenotype (in which resistance is mediated by a methylase encoded by the ermTR gene). Both ketolides were less active against erythromycin-resistant S. pyogenes strains with the cMLS phenotype or the iMLS-A subtype (where resistance is mediated by a methylase encoded by the ermAM gene), these strains ranging in phenotype from the upper limits of susceptibility to low-level resistant.     

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

Streptococcus pyogenes strains inducibly resistant (iMLS phenotype) to macrolide, lincosamide, and streptogramin B (MLS) antibiotics can be subdivided into three phenotypes: iMLS-A, iMLS-B, and iMLS-C. This study focused on inducibly erythromycin-resistant S. pyogenes strains of the iMLS-B and iMLS-C types, which are very similar and virtually indistinguishable in a number of phenotypic and genotypic features but differ clearly in their degree of resistance to MLS antibiotics (high in the iMLS-B type and low in the iMLS-C type). As expected, the iMLS-B and iMLS-C test strains had the erm(A) methylase gene; the iMLS-A and the constitutively resistant (cMLS) isolates had the erm(B) methylase gene; and a control M isolate had the mef(A) efflux gene. mre(A) and msr(A), i.e., other macrolide efflux genes described in gram-positive cocci, were not detected in any test strain. With a radiolabeled erythromycin method for determination of the intracellular accumulation of the drug in the absence or presence of an efflux pump inhibitor, active efflux of erythromycin was observed in the iMLS-B isolates as well as in the M isolate, whereas no efflux was demonstrated in the iMLS-C isolates. By the triple-disk (erythromycin plus clindamycin and josamycin) test, performed both in normal test medium and in the same medium supplemented with the efflux pump inhibitor, under the latter conditions iMLS-B and iMLS-C strains were no longer distinguishable, all exhibiting an iMLS-C phenotype. In conjugation experiments with an iMLS-B isolate as the donor and a Rif(r) Fus(r) derivative of an iMLS-C isolate as the recipient, transconjugants which shared the iMLS-B type of the donor under all respects, including the presence of an efflux pump, were obtained. These results indicate the existence of a novel, transferable efflux system, not associated with mef(A) or with other known macrolide efflux genes, that is peculiar to iMLS-B strains. Whereas the low-level resistance of iMLS-C strains to MLS antibiotics is apparently due to erm(A)-encoded methylase activity, the high-level resistance of iMLS-B strains appears to depend on the same methylase activity plus the new efflux system.     

In vitro activity of the new ketolide telithromycin compared with those of macrolides against Streptococcus pyogenes: influences of resistance mechanisms and methodological factors

One hundred and seven clinical isolates of Streptococcus pyogenes, 80 susceptible to macrolides and 27 resistant to erythromycin A (MIC >0.5 microgram/ml), were examined. The erythromycin A-lincomycin double-disk test assigned 7 resistant strains to the M-phenotype, 8 to the inducible macrolide, lincosamide, and streptogramin B resistance (iMLS(B)) phenotype, and 12 to the constitutive MLS(B) resistance (cMLS(B)) phenotype. MICs of erythromycin A, clarithromycin, azithromycin, roxithromycin, and clindamycin were determined by a broth microdilution method. MICs of telithromycin were determined by three different methods (broth microdilution, agar dilution, and E-test methods) in an ambient air atmosphere and in a 5 to 6% CO(2) atmosphere. Erythromycin A resistance genes were investigated by PCR in the 27 erythromycin A-resistant isolates. MICs of erythromycin A and clindamycin showed six groups of resistant strains, groups A to F. iMLS(B) strains (A, B, and D groups) are characterized by two distinct patterns of resistance correlated with genotypic results. A- and B-group strains were moderately resistant to 14- and 15-membered ring macrolides and highly susceptible to telithromycin. All A- and B-group isolates harbored erm TR gene, D-group strains, highly resistant to macrolides and intermediately resistant to telithromycin (MICs, 1 to 16 microgram/ml), were all characterized by having the ermB gene. All M-phenotype isolates (C group), resistant to 14- and 15-membered ring macrolides and susceptible to clindamycin and telithromycin, harbored the mefA gene. All cMLS(B) strains (E and F groups) with high level of resistance to macrolides, lincosamide, and telithromycin had the ermB gene. The effect of 5 to 6% CO(2) was remarkable on resistant strains, by increasing MICs of telithromycin from 1 to 6 twofold dilutions against D-E- and F-group isolates.     

Activities of 16-membered ring macrolides and telithromycin against different genotypes of erythromycin-susceptible and erythromycin-resistant Streptococcus pyogenes and Streptococcus pneumoniae

OBJECTIVES: To test four 16-membered macrolides (josamycin, spiramycin, midecamycin and rokitamycin) along with other compounds in the same class (erythromycin, clarithromycin, roxithromycin and azithromycin) plus clindamycin and telithromycin, against Streptococcus pyogenes and Streptococcus pneumoniae isolates with well-characterized resistance genotypes. METHODS: Four hundred and eighty-six isolates of S. pyogenes and 375 isolates of S. pneumoniae were assayed for their macrolide susceptibilities and investigated by PCR to detect their different erythromycin resistance genes. All strains had been isolated over the period 2002-2003 from specimens of different human origin obtained in 14 different Italian centres. RESULTS: All 16-membered macrolides showed very low MICs (MIC(50)s and MIC(90)s, < or =0.06-0.5 mg/L) for the erythromycin-susceptible isolates and for those with the M phenotype, but the telithromycin MICs for the M-type isolates were at least four times higher (MIC(90)s, 0.5 mg/L). In S. pyogenes, the MIC(50)s of 16-membered macrolides for the cMLS(B) isolates were > or = 256 mg/L, whereas that for telithromycin was 4 mg/L; the MIC(50)s of 16-membered macrolides and telithromycin ranged from < or = 0.06 to 0.5 mg/L for the iMLS(B) isolates with erm(A) and from 0.12 to > or = 256 mg/L for those with erm(B). In S. pneumoniae, the MIC(50)s of the 16-membered macrolides for the cMLS(B) isolates ranged from 0.5 to 128 mg/L, whereas for the iMLS(B) isolates their values ranged from < or = 0.06 to 4 mg/L; the MIC(50)s and MIC(90)s of telithromycin for both the cMLS(B) and the iMLS(B) isolates ranged from < or = 0.06 to 0.12 mg/L. CONCLUSIONS: MICs ranged for all the drugs, except telithromycin, from < or = 0.06 to > or = 256 mg/L, with 15% to 30% resistant S. pyogenes for all drugs tested except clindamycin (8%) and telithromycin (5.4%) and 10% to 40% resistant S. pneumoniae for all drugs tested except telithromycin (0.3%). In both S. pyogenes and S. pneumoniae, erythromycin resistance related to a mef gene meant that telithromycin MICs were definitely higher than in erythromycin-susceptible isolates, although telithromycin susceptibility was preserved in all cases. In S. pyogenes, the activity of both 16-membered macrolides and telithromycin against the iMLS(B) strains proved to be dependent on the erm gene involved, being greater against isolates with erm(A).     

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

The purpose of the present study was to determine the antimicrobial resistance among Streptococcus pyogenes in Bavaria, Germany. Five hundred and forty isolates of S. pyogenes were collected from patients with tonsillopharyngitis. Of these, 425 isolates were obtained from children and 115 from adult patients. All isolates were tested for susceptibility to macrolides, clindamycin, penicillin and 10 other commonly prescribed antimicrobial agents, using broth microdilution tests. All isolates were fully susceptible to penicillin, amoxicillin and cephalosporins; 16.1% of the isolates were resistant to tetracycline. MIC(90) values of erythromycin, clarithromycin, azithromycin and josamycin were 16, 4, 16 and 0.5 mg/L. The overall resistance rate of S. pyogenes to erythromycin, clarithromycin and azithromycin was 13.3%. All isolates resistant to erythromycin were also resistant to clarithromycin and azithromycin, and vice versa. Erythromycin resistance rates were higher in adult patients (19.1%) than in children (11.8%). The resistance rate to josamycin was only 1.5%, a value similar to that of clindamycin (1.1%). Among the 72 erythromycin-resistant isolates the M phenotype of macrolide resistance predominated (78%), while percentages of cMLS(B) (8%) and iMLS(B) (14%) phenotypes were low. Of the iMLS(B) strains (n = 10), the majority were of the subtype C (n = 8). The M phenotype was associated with a low, and the iMLS(B)-C phenotype with a high, rate of resistance to tetracycline. Conclusively, present data point to rising macrolide resistance among S. pyogenes in Bavaria.     

High prevalence of inducible erythromycin resistance among Streptococcus bovis isolates in Taiwan.

Susceptibilities to 13 antimicrobial agents were determined by measurement of MICs for 60 isolates of Streptococcus bovis from blood cultures. Thirty-eight isolates (63.3%) had high-level resistance to erythromycin (MICs, >or=128 microg/ml). Among the 38 erythromycin-resistant strains, 21 isolates (55%) had inducible resistance to macrolides-lincosamides-streptogramin B (iMLS isolates) and 17 (45%) had constitutive resistance to macrolides-lincosamides-streptogramin B (cMLS isolates). Tetracycline resistance was also found among all of the erythromycin-resistant strains. None of the strains displayed resistance to penicillin, chloramphenicol, or vancomycin. Detection of erythromycin resistance genes by PCR and sequencing indicated that all 17 cMLS isolates were positive for the ermB gene and that 7 of 21 iMLS isolates carried the ermB gene and the remaining 14 iMLS isolates carried the ermT gene. Sequence analysis of amplified partial ermB fragments (594 bp) from S. bovis isolates revealed a 99.8% nucleotide identity and a 100% amino acid homology compared with the sequences from gene banks. The sequences of amplified fragments with primers targeted for ermC were shown to be very similar to that of ermGT (ermT) from Lactobacillus reuteri (98.5% nucleotide identity). This is the first report to describe the detection of the ermT class of erythromycin resistance determinants in S. bovis. The high rate of inducible erythromycin resistance among S. bovis isolates in Taiwan was not reported before. The iMLS S. bovis isolates were shown to be heterogeneous by randomly amplified polymorphic DNA analysis. These results indicate that the prevalence of inducible erythromycin resistance in S. bovis in Taiwan is very high and that most of the resistant strains carry the ermT or the ermB gene.     

Macrolide-lincosamide-streptogramin B (MLS) resistance in cutaneous propionibacteria: definition of phenotypes

Erythromycin-resistant propionibacteria isolated from the skin of antibiotic-treated acne patients were found to express four different patterns of resistance to a set of eight MLS antibiotics. The majority of isolates (48/89 strains) were constitutively resistant to 14- and 16-membered ring macrolide, lincosamide and streptogramin B-type antibiotics. MICs of josamycin (0.5-16 mg/l) and spiramycin (0.5-128 mg/l) were lower than those of erythromycin, oleandomycin and tylosin (64 to less than 512 mg/l). Two strains of Propionibacterium granulosum exhibited inducible MLS resistance. Both 14- and 16-membered ring macrolides and virginiamycin S induced clindamycin resistance in these strains. Fifteen isolates demonstrated a similar phenotype to the inducible strains but were non-inducible by erythromycin. A fourth group of strains demonstrated high level resistance to all five macrolides tested (MIC greater than or equal to 128 mg/l) but were sensitive to virginiamycin S. The phenotype displayed by these strains is not compatible with the expression of methylase genes as currently known, nor with the action of an erythromycin esterase which hydrolyses only 14-membered ring macrolides. The resistance patterns of 12 isolates could not be classified into any of the above phenotypic classes. Therefore, the majority of erythromycin resistant propionibacteria express MLS resistance which is phenotypically similar to that coded for by several well characterized RNA methylase (erm) genes.     

Prevalence and phenotypes of erythromycin-resistant Streptococcus pneumoniae in Shanghai, China

Bacterial resistance of Streptococcus pneumoniae against erythromycin and clindamycin and resistance phenotypes of erythromycin-resistant Streptococcus pneumoniae were investigated. The MICs of erythromycin and clindamycin against 345 strains of Streptococcus pneumoniae were tested with agar dilution method; the phenotypes of erythromycin-resistant Streptococcus pneumoniae were detected by double-disk test. One hundred and eighty-three and 171 of 345 (53.0% and 49.6%) of isolates had MICs > or =1 microg/ml for erythromycin and for clindamycin. Among erythromycin-resistant Streptococcus pneumoniae, the percentage of cMLS, iMLS and M phenotype was 90.3% (159/176), 5.7% (10/176) and 4.0% (7/176), respectively. The incidence of erythromycin-resistant Streptococcus pneumoniae is very high in Shanghai. The main phenotype is cMLS.     

Telithromycin and quinupristin-dalfopristin resistance in clinical isolates of Streptococcus pyogenes: SMART Program 2001 Data

This study evaluated the current status of antimicrobial resistance in clinical isolates of Streptococcus pyogenes in Taiwan as part of the SMART (Surveillance from Multicenter Antimicrobial Resistance in Taiwan) program. In 2001, 419 different isolates of S. pyogenes, including 275 from respiratory secretions, 87 from wound pus, and 31 from blood, were collected from nine hospitals in different parts of Taiwan. MICs of 23 antimicrobial agents were determined at a central location by the agar dilution method. All of the isolates were susceptible to penicillin (MIC at which 90% of the isolates were inhibited [MIC(90)], moxifloxacin > ciprofloxacin = levofloxacin = gatifloxacin > gemifloxacin) demonstrated potent activity against nearly all of the isolates of S. pyogenes tested. Thirty-two isolates (8%) were not susceptible to quinupristin-dalfopristin. Seventeen percent of isolates had telithromycin MICs of >or=1 microg/ml, and all of these isolates exhibited erythromycin MICs of >or=32 microg/ml. The high prevalence of resistance to telithromycin (which is not available in Taiwan) limits its potential use in the treatment of S. pyogenes infections, particularly in areas with high rates of macrolide resistance.     

Heterogeneity of macrolide-lincosamide-streptogramin B resistance phenotypes in enterococci

We determined the macrolide resistance phenotypes of 241 clinical isolates of erythromycin-resistant enterococci (MICs, > or = 1 microg/ml), including 147 Enterococcus faecalis strains and 94 Enterococcus faecium strains, collected from a hospital in Seoul, Korea, between 1999 and 2000. By the erythromycin (40 micro g)-josamycin (100 microg) double-disk test, 93 strains were assigned to the constitutive macrolide, lincosamide, and streptogramin B (MLS(B)) resistance (cMLS(B)) phenotype, and the remaining 148 strains were assigned to the inducible MLS(B) resistance (iMLS(B)) phenotype. Of the strains with the iMLS(B) phenotype, 36 exhibited a reversibly inducible MLS(B) (riMLS(B)) phenotype, i.e., blunting of the erythromycin zone of inhibition, which indicates that the 16-membered-ring macrolide josamycin is a more effective inducer than the 14-membered-ring macrolide erythromycin. Sequence analysis of the regulatory regions of the erm(B) genes from all of the strains exhibiting the riMLS(B) phenotype revealed not only erm(Bv) [where v represents variant; previously erm(AMR)] (n = 13), as reported previously, but also three kinds of erm(B) variants, which were designated erm(Bv1) (n = 17), erm(Bv2) (n = 3), and erm(Bv3) (n = 3), respectively. In lacZ reporter gene assays of these variants, the 16-membered-ring macrolide tylosin had stronger inducibility than erythromycin at > or = 0.1 microg/ml. These findings highlight the versatility of erm(B) in induction specificity.     

Phenotypic and molecular characterization of tetracycline- and erythromycin-resistant strains of Streptococcus pneumoniae

Sixty-five clinical isolates of Streptococcus pneumoniae, all collected in Italy between 1999 and 2002 and resistant to both tetracycline (MIC, >or=8 microg/ml) and erythromycin (MIC, >or=1 microg/ml), were investigated. Of these strains, 11% were penicillin resistant and 23% were penicillin intermediate. With the use of the erythromycin-clindamycin-rokitamycin triple-disk test, 14 strains were assigned to the constitutive (cMLS) phenotype of macrolide resistance, 44 were assigned to the partially inducible (iMcLS) phenotype, 1 was assigned to the inducible (iMLS) phenotype, and 6 were assigned to the efflux-mediated (M) phenotype. In PCR assays, 64 of the 65 strains were positive for the tetracycline resistance gene tet(M), the exception being the one M isolate susceptible to kanamycin, whereas tet(K), tet(L), and tet(O) were never found. All cMLS, iMcLS, and iMLS isolates had the erythromycin resistance gene erm(B), and all M phenotype isolates had the mef(A) or mef(E) gene. No isolate had the erm(A) gene. The int-Tn gene, encoding the integrase of the Tn916-Tn1545 family of conjugative transposons, was detected in 62 of the 65 test strains. Typing assays showed the strains to be to a great extent unrelated. Of 16 different serotypes detected, the most numerous were 23F (n = 13), 19A (n = 10), 19F (n = 9), 6B (n = 8), and 14 (n = 6). Of 49 different pulsed-field gel electrophoresis types identified, the majority (n = 39) were represented by a single isolate, while the most numerous type included five isolates. By high-resolution restriction analysis of PCR amplicons with four endonucleases, the tet(M) loci from the 64 tet(M)-positive pneumococci were classified into seven distinct restriction types. Overall, a Tn1545-like transposon could reasonably account for tetracycline and erythromycin resistance in the vast majority of the pneumococci of cMLS, iMcLS, and iMLS phenotypes, whereas a Tn916-like transposon could account for tetracycline resistance in most M phenotype strains.     

In vitro activities of two ketolides, HMR 3647 and HMR 3004, against gram-positive bacteria

The in vitro activities of two new ketolides, HMR 3647 and HMR 3004, were tested by the agar dilution method against 280 strains of gram-positive bacteria with different antibiotic susceptibility profiles, including Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Streptococcus spp. (group A streptococci, group B streptococci, Streptococcus pneumoniae, and alpha-hemolytic streptococci). Seventeen erythromycin-susceptible (EMs), methicillin-susceptible S. aureus strains were found to have HMR 3647 and HMR 3004 MICs 4- to 16-fold lower than those of erythromycin (MIC at which 50% of isolates were inhibited [MIC50] [HMR 3647 and HMR 3004], 0.03 microgram/ml; range, 0.03 to 0.06 microgram/ml; MIC50 [erythromycin], 0.25 microgram/ml; range, 0.25 to 0.5 microgram/ml). All methicillin-resistant S. aureus strains tested were resistant to erythromycin and had HMR 3647 and HMR 3004 MICs of > 64 micrograms/ml. The ketolides were slightly more active against E. faecalis than against E. faecium, and MICs for individual strains varied with erythromycin susceptibility. The MIC50s of HMR 3647 and HMR 3004 against Ems enterococci (MIC < or = 0.5 microgram/ml) and those enterococcal isolates with erythromycin MICs of 1 to 16 micrograms/ml were 0.015 microgram/ml. E. faecalis strains that had erythromycin MICs of 128 to > 512 micrograms/ml showed HMR 3647 MICs in the range of 0.03 to 16 micrograms/ml and HMR 3004 MICs in the range of 0.03 to 64 micrograms/ml. In the group of E. faecium strains for which MICs of erythromycin were > or = 512 micrograms/ml, MICs of both ketolides were in the range of 1 to 64 micrograms/ml, with almost all isolates showing ketolide MICs of < or = 16 micrograms/ml. The ketolides were also more active than erythromycin against group A streptococci, group B streptococci, S. pneumoniae, rhodococci, leuconostocs, pediococci, lactobacilli, and diphtheroids. Time-kill studies showed bactericidal activity against one strain of S. aureus among the four strains tested. The increased activity of ketolides against gram-positive bacteria suggests that further study of these agents for possible efficacy against infections caused by these bacteria is warranted.     

溶脲脲原体对大环内酯类药物的敏感性分析

目的：检测溶脲脲原体(Uu)对14环(红霉素和罗红霉素)、15环(阿奇霉素)和16环(交沙霉素和吉他霉素)大环内酯类药物的敏感性，为临床合理用药提供参考依据。方法：采用微量肉汤稀释法检测了5种大环内酯类药物对203株Uu的最低抑菌浓度(MIC)。结果：203株Uu对红霉素、罗红霉素、阿奇霉素、交沙霉素和吉他霉素的耐药率分别为：11．8％、7．4％、6．9％、3．9％和3．5％。在5种药物中，交沙霉素和吉他霉素抗Uu活性最强，MIC50分别为0．125mg／L和0．5mg／L，MIC90分别为0．5mg／L和1mg／L，其次为阿奇霉素，MIC50和MIC90分别为2mg／L和4mg／L，红霉素和罗红霉素抗Uu活性较弱，MIC50均为4mg／L，MIC90均为8mg／L.结论：Uu对大环内酯类药物存在不同程度的耐药；16环大环内酯类药物交沙霉素和吉他霉素抗Uu活性强于14环和15环大环内酯类药物。     

Comparative in vitro activities of new 14-, 15-, and 16-membered macrolides.

The in vitro activities of several 14-, 15- and 16-membered macrolides were compared with that of erythromycin. In general, 14-membered macrolides such as erythromycin, clarithromycin, and flurithromycin were more active against streptococci and Bordetella pertussis than was the 15-membered macrolide azithromycin, which was more active than 16-membered macrolides such as miocamycin and rokitamycin. Clarithromycin was the most active compound against Streptococcus pyogenes, pneumococci, Listeria monocytogenes, and Corynebacterium species. Legionella pneumophila was most susceptible to miocamycin, clarithromycin, and rokitamycin. Branhamella catarrhalis, Neisseria gonorrhoeae, and Haemophilus influenzae were most susceptible to azithromycin. Azithromycin and dirithromycin were the most active compounds against Campylobacter jejuni. MICs of 16-membered macrolides for strains expressing inducible-type resistance to erythromycin were less than or equal to 1 microgram/ml, whereas none of the compounds had activity against strains expressing constitutive-type resistance. The MICs of roxithromycin, miocamycin, rokitamycin, and josamycin increased in the presence of human serum, whereas MICs of the other compounds either were unchanged or decreased.     

Increased activity of 16-membered lactone ring macrolides against erythromycin-resistant Streptococcus pyogenes and Streptococcus pneumoniae: characterization of South African isolates

The susceptibility of 40 erythromycin-resistant isolates of Streptococcus pyogenes and 40 multiply-resistant isolates of Streptococcus pneumoniae to six macrolide antibiotics, representing 14-, 15- and 16-membered lactone ring structures, was tested. The genetic basis for macrolide resistance in the strains was also determined. Both erm and mef determinants were encountered in the 36 S. pneumoniae isolates tested, but only mef in the five S. pyogenes isolates tested. All isolates showed cross-resistance among the 14-membered macrolides erythromycin, clarithromycin and roxithromycin and the 15-membered macrolide, azithromycin. However, the erythromycin-resistant S. pyogenes isolates retained full susceptibility to spiramycin and josamycin (16-membered agents). These latter two antibiotics were also more active than the other macrolides against erythromycin-resistant S. pneumoniae isolates, especially josamycin which was 8-64 times more active than erythromycin; spiramycin was only two to eight times more active than erythromycin.     

Activities of a new fluoroketolide, HMR 3787, and its (des)-fluor derivative RU 64399 compared to those of telithromycin, erythromycin A, azithromycin, clarithromycin, and clindamycin against macrolide-susceptible or -resistant Streptococcus pneumoniae and S. pyogenes

Activities of HMR 3787 and RU 64399 were compared to those of three macrolides, telithromycin, and clindamycin against 175 Streptococcus pneumoniae isolates and 121 Streptococcus pyogenes isolates. HMR3787 and telithromycin were the most active compounds tested against pneumococci. Telithromycin and RU 64399 were equally active against macrolide-susceptible (MICs, 0.008 to 0.06 microg/ml) and -resistant S. pyogenes isolates, but HMR 3787 had lower MICs for ermB strains.     

New macrolides active against Streptococcus pyogenes with inducible or constitutive type of macrolide-lincosamide-streptogramin B resistance

Macrolide-resistant bacteria can be classified as inducibly resistant or constitutively resistant. Inducibly resistant bacteria are resistant to 14-membered macrolides, such as erythromycin and clarithromycin (A-56268), but are susceptible to the 16-membered macrolides, such as tylosin and spiramycin, as well as to clindamycin. Constitutively resistant bacteria are resistant to macrolide-lincosamide-streptogramin B antibiotics. In this study, the MICs of several erythromycin and clarithromycin analogs against macrolide-susceptible and macrolide-resistant Streptococcus pyogenes strains were determined. Four 11,12-carbamate analogs of clarithromycin had lower MICs than erythromycin did against S. pyogenes with the inducible or constitutive type of macrolide-lincosamide-streptogramin B resistance. Five 11,12-carbonate analogs of erythromycin with modifications at the 4" position of cladinose had lower MICs than did erythromycin against S. pyogenes with the constitutive type of resistance, and one of these compounds, which had a naphthyl-glycyl substitution at the 4" position, had a lower MIC than erythromycin against both the inducibly resistant and constitutively resistant strains. Two analogs of erythromycin with a modification on the 4" position of cladinose had lower MICs than erythromycin did against the constitutively resistant organisms but not against the inducibly resistant organisms. Thus, 14-membered macrolides can be modified so as to confer a low MIC when tested in vitro.     

In vitro activity of telithromycin (HMR3647), a new ketolide, against clinical isolates of Mycoplasma pneumoniae in Japan

The in vitro activity of telithromycin (HMR3647), a new ketolide, against Mycoplasma pneumoniae was determined by the broth microdilution test using 41 clinical isolates obtained in Japan, as compared with those of five macrolides (erythromycin, clarithromycin, roxithromycin, azithromycin, and josamycin), minocycline, and levofloxacin. Telithromycin was less potent than azithromycin, but it was more active than four other macrolides, minocycline, and levofloxacin; its MICs at which 50 and 90% of the isolates tested were inhibited were both 0.00097 microg/ml, justifying clinical studies to determine its efficacy for treatment of M. pneumoniae.     

Comparative antianaerobic activities of the ketolides HMR 3647 (RU 66647) and HMR 3004 (RU 64004).

HMR 3647 (RU 66647) and HMR 3004 (RU 64004), two ketolides, had MICs at which 50% of the strains are inhibited (MIC50s) of 0.06 to 0.125 microg/ml and MIC90s of 16.0 microg/ml against 352 anaerobes. MIC50s and MIC90s of erythromycin, azithromycin, clarithromycin, and roxithromycin were 0.5 to 2.0 microg/ml and 32.0 to >64.0 microg/ml, respectively. HMR 3647 and HMR 3004 were more active against non-Bacteroides fragilis-group anaerobes (other than Fusobacterium mortiferum, Fusobacterium varium, and Clostridium difficile).     

Characterisation and molecular cloning of the novel macrolide-streptogramin B resistance determinant from Staphylococcus epidermidis

A total of 110 staphylococcal isolates from human skin were found to express a novel type of erythromycin resistance. The bacteria were resistant to 14-membered ring macrolides (MIC 32-128 mg/l) but were sensitive to 16-membered ring macrolides and lincosamides. Resistance to type B streptogramins was inducible by erythromycin. A similar phenotype, designated MS resistance, was previously described in clinical isolates of coagulase-negative staphylococci from the USA. In the UK, MS resistance is widely distributed in coagulase-negative staphylococci but was not detected in 100 erythromycin resistant clinical isolates of Staphylococcus aureus. Tests for susceptibility to a further 16 antibiotics failed to reveal any other selectable marker associated with the MS phenotype. Plasmid pattern analysis of 48 MS isolates showed considerable variability between strains and no common locus for the resistance determinant. In one strain of S. epidermidis co-resistance to tetracycline, penicillin and erythromycin (MS) was associated with a 31.5 kb plasmid, pUL5050 which replicated and expressed all three resistances when transformed into S. aureus RN4220. The MS resistance determinant was localised to a 1.9 kb fragment which was cloned on to the high-copy-number vector, pSK265. A constitutive mutant of S. aureus RN4220 containing the 1.9 kb fragment remained sensitive to clindamycin. This observation, together with the concentration-dependent induction (optimum 5 mg/l of erythromycin) of virginiamycin S resistance suggests that the MS phenotype is not due to altered expression of MLS resistance determinants (erm genes) but probably occurs via a different mechanism.