Tigecycline (GAR-936) activity against Streptococcus gallolyticus (bovis) and viridans group streptococci

Viridans group streptococci including Streptococcus gallolyticus (formerly S. bovis) represent serious invasive pathogens often associated with endocarditis or sepsis among immunocompromised or cancer patients. Tigecycline (GAR-936), the first clinically studied glycylcycline, has a potent gram-positive activity with a potential treatment option for these streptococcal infections. The studied collection (848 strains) included 100 isolates each of Streptococcus anginosus, Streptococcus constellatus, Streptococcus intermedius, Streptococcus mitis, Streptococcus oralis, Streptococcus salivarius, Streptococcus sanguis, and fewer strains of S. gallolyticus (98 strains) and Streptococcus mutans (50 strains). These strains were isolated from patients on 3 continents in the SENTRY Antimicrobial Surveillance Program and tested for susceptibility and interpreted by Clinical and Laboratory Standards Institute broth microdilution methods and criteria (< or = 0.25 microg/mL for tigecycline per US Food and Drug Administration). Penicillin susceptibility rates for the entire collection varied from 61% (S. sanguis) to 98% (S. constellatus), and macrolide susceptibility was also compromised (49-88%; average, 69%). Tigecycline was active against all isolates tested, in contrast to tetracycline resistance rates of 8-66%, and highest for S. gallolyticus. In conclusion tigecycline was quite active against bacteremic isolates of viridans group streptococci species and S. gallolyticus with an overall MIC90 at < or = 0.06 microg/mL; the highest MIC was only 0.25 microg/mL.     

Activity of DX-619 compared to other agents against viridans group streptococci, Streptococcus bovis, and Cardiobacterium hominis

Against 198 viridans group streptococci, 25 Streptococcus bovis strains, and 5 Cardiobacterium hominis strains, MICs of DX-619, a des-F(6)-quinolone, were between 0.004 and 0.25 microg/ml. These MICs were lower than those of other quinolones (< or = 0.008 to > 32 microg/ml). Beta-lactam MICs were between < or = 0.008 and 16 microg/ml. Azithromycin resistance was found in most species, while most were telithromycin susceptible. Glycopeptides and linezolid were active against viridans group strains but inactive against C. hominis.     

In vitro activity of telithromycin against viridans group streptococci and Streptococcus bovis isolated from blood: antimicrobial susceptibility patterns in different groups of species

The in vitro activities of penicillin, erythromycin, clindamycin, and telithromycin were determined against 155 viridans group streptococci (VGS) and 18 Streptococcus bovis blood isolates. Heterogeneity in the susceptibility patterns and macrolide resistance phenotypes and genotypes in the different groups of VGS was detected. We found seven telithromycin-resistant S. bovis isolates all harboring the erm(B) gene.     

In vitro evaluation of AZD2563, a new oxazolidinone,tested against beta-haemolytic and viridans group streptococci

Linezolid was the first clinically applied agent from the oxazolidinone class, and AZD2563, a new agent, is described here. Five hundred and twenty-five streptococcal isolates were tested, including beta-haemolytic (266) and viridans group (259) species. MIC(50)/MIC(90)/% susceptible (susceptibility breakpoint <2 mg/L of AZD2563) results were, for beta-haemolytic species: AZD2563 (1/2/100), linezolid (1/2/100), quinupristin-dalfopristin (0.25/0.25/100), vancomycin (0.25/0.5/100) and levofloxacin (0.5/1/99); for viridans group species: AZD2563 (0.5/1/100), linezolid (1/1/100), quinupristin-dalfopristin (0.5/1/99), vancomycin (0.5/0.5/100) and levofloxacin (1/1/98). The modal MICs of AZD2563 and linezolid were 0.5 or 1 mg/L and 1 mg/L, respectively. AZD2563 activity screening against these non-pneumococcal streptococci indicated a slightly greater potency of AZD2563 when compared with linezolid. All AZD2563 MICs were <2 mg/L.     

Distribution of subclasses mefA and mefE of the mefA gene among clinical isolates of macrolide-resistant (M-phenotype) Streptococcus pneumoniae, viridans group streptococci, and Streptococcus pyogenes

The distribution of subclasses mefA and mefE of the mefA gene among 116 M-phenotype streptococci was as follows: pneumococci (38 strains had mefE and 4 mefA), viridans streptococci (49 mefE and 1 mefA), and Streptococcus pyogenes (24 mefA). Spain(9V)-3-14 and England(14)-9 clones of serotype 14 were dominant among pneumococci.     

Activities of potential therapeutic and prophylactic antibiotics against blood culture isolates of viridans group streptococci from neutropenic patients receiving ciprofloxacin.

All 47 sequential blood culture isolates of viridans group streptococci obtained from febrile neutropenic patients receiving quinolone prophylaxis were susceptible to vancomycin, teicoplanin, and imipenem. Resistance to benzylpenicillin (MIC for 50% of isolates [MIC50], 0.125 microgram/ml) and ceftazidime (MIC50, 4 micrograms/ml) was common. Most isolates were susceptible to amoxicillin, co-amoxiclav (amoxicillin-clavulanic acid at a 2:1 ratio by weight), azlocillin, clarithromycin, and erythromycin, with azithromycin showing comparable activity. The MIC90 of sparfloxacin was 1 microgram/ml; those for ciprofloxacin and ofloxacin were > 16 and 16 micrograms/ml, respectively.     

In vitro activities of garenoxacin (BMS-284756) against Streptococcus pneumoniae, viridans group streptococci, and Enterococcus faecalis compared to those of six other quinolones

The activity of garenoxacin, a new quinolone, was determined in comparison with other quinolones against different strains of S. pneumoniae, viridans group streptococci (VGS), and Enterococcus faecalis. Strains were quinolone-susceptible clinical isolates and quinolone-resistant strains with defined mechanisms of resistance obtained from either clinical isolates or derivatives of S. pneumoniae R6. Clinical quinolone-susceptible strains of S. pneumoniae, VGS and E. faecalis showed garenoxacin MICs within a range of 0.03 microg/ml to 0.25 micro g/ml. Garenoxacin MICs increased two- to eightfold when one mutation was present in the ParC quinolone resistance-determining region (QRDR), fourfold when one mutation was present in the GyrA QRDR (S. pneumoniae), 8- to 64-fold when two or three mutations were associated in ParC and GyrA QRDR, and 2,048-fold when two mutations were present in both the GyrA and ParC QRDRs (Streptococcus pneumoniae). Increased active efflux had a moderate effect on garenoxacin MICs for S. pneumoniae and VGS. Against S. pneumoniae, garenoxacin behaved like moxifloxacin and sparfloxacin, being more affected by a single gyrA mutation than by a single parC mutation. Although garenoxacin was generally two- to fourfold more active than moxifloxacin against the different wild-type or mutant strains of S. pneumoniae, VGS, and E. faecalis, it was two- to fourfold less active than gemifloxacin. At four times the respective MIC for each strain, the bactericidal effect of garenoxacin, observed at 6 h for S. pneumoniae and at 24 h for S. oralis and E. faecalis, was not influenced by the presence of mutation either in the ParC or in both the ParC and GyrA QRDRs.     

Antimicrobial activity and spectrum of sparfloxacin tested against erythromycin-resistant Streptococcus pneumoniae isolates

Recognition of a worldwide increase of penicillin-resistant Streptococcus pneumoniae and cross-resistance to other classes of antimicrobials have placed a great urgency on the need for new antimicrobial agents. Sparfloxacin, a novel pyridone carboxylic acid fluoroquinolone derivative was evaluated and compared to six other compounds for antimicrobial activity against erythromycin-resistant pneumococci (50 strains). The Etest susceptibility testing method was used to inoculate Mueller-Hinton agar supplemented with 5% sheep blood. There was extensive cross-resistance between erythromycin, clarithromycin (94%), and azithromycin (100%), but no cross-resistance was detected between macrolides/azalides and sparfloxacin (all strains susceptible at ⩽1.0 μg/ml). Sparfloxacin (MIC₉₀, 1 μg/ml) was four-fold more active than ciprofloxacin and ofloxacin (MIC₉₀, 4 μg/ml). Sparfloxacin appears to possess excellent in vitro activity against erythromycin-resistant S. pneumoniae that were often highly resistant to beta-lactams, and further studies are recommended to investigate its in vivo efficacy against these multi-resistant organisms.     

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

OBJECTIVES: We studied the species distribution and antimicrobial susceptibility of viridans streptococci (VS) isolates causing nosocomial bloodstream infections (BSIs) in Finnish hospitals. PATIENTS AND METHODS: Patients with nosocomial BSIs due to VS were identified through a hospital-wide prospective laboratory-based surveillance in two university and two regional hospitals during September 1998-August 2001. Isolates of VS were sent to the reference laboratory for species confirmation and antimicrobial susceptibility testing. RESULTS: A total of 2038 nosocomial BSIs were identified; 108 (5%) of the BSIs were caused by VS. Of the VS BSIs, 66% were in patients with a haematological malignancy, 14% in patients with a solid tumour and 18% in patients who had undergone surgery preceding the infection. The most common species group identified was Streptococcus mitis (82%). High-level penicillin resistance (> or = 4 mg/L) and cefotaxime resistance (> or = 4mg/L) were present in 5% and 4% of isolates, respectively; both were detected only in haematological patients. However, in non-haematological patients, resistance to erythromycin (17%), and reduced susceptibility to levofloxacin (14%) and penicillin (19%) were common. CONCLUSIONS: The resistance problems in VS are not limited to haematological patients. These findings may have significant clinical implications in the choice of both empirical antibiotic and antimicrobial prophylaxis regimens.     

Genetic basis of antibiotic resistance in clinical isolates of Streptococcus gallolyticus (Streptococcus bovis)

Among 128 Streptococcus gallolyticus (Streptococcus bovis) isolates, 77.7% were resistant to tetracyclines and contained tet(M) and/or tet(L) and/or tet(O). A total of 59.4% had macrolide resistance and contained erm(B) and, rarely, mef(A). Among the one-third of isolates highly resistant to kanamycin and streptomycin, most harbored aphA3 and aad-6 genes.     

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

Oropharyngeal samples from 60 hospitalized patients (30 fluoroquinolone [FQ]-treated and 30 non-FQ-treated patients) and 30 untreated nonhospitalized healthy control subjects yielded 20 isolates of viridans group streptococci with reduced susceptibility to FQ, mostly from the hospitalized patients. An efflux phenotype was commonly encountered, expressed either alone or with topoisomerase mutations. Interspecies transfer of the efflux phenotype was demonstrated via transformation of Streptococcus pneumoniae R6 with DNA from S. mitis and S. oralis.     

Activities of new fluoroquinolones, ketolides, and other antimicrobials against blood culture isolates of viridans group streptococci from across Canada, 2000

The rates of nonsusceptibility to penicillin, erythromycin, and clindamycin of 191 blood culture isolates of viridans group streptococci collected from across Canada in 2000 were 36, 42, and 10%, respectively. Although 8% of the strains were resistant to ciprofloxacin (MIC >or= 4 microg/ml), the MICs of gemifloxacin, BMS 284756, telithromycin, and ABT 773 at which 90% of the strains were inhibited were 0.06, 0.06, 0.12, and 0.03 microg/ml, respectively.     

Enhanced activity of the combination of penicillin G and gentamicin against penicillin-resistant viridans group streptococci.

We evaluated the effects of the combination of penicillin G and gentamicin against 10 penicillin-resistant bacteremic isolates of viridans group streptococci for which the MICs of penicillin were 4 to 64 micrograms/ml. In time-kill studies, the combination resulted in more killing of eight isolates for which the MICs of penicillin were from 8 to 64 micrograms/ml than any of the antimicrobial agents tested alone. In general, clearly enhanced antimicrobial activity was observed with the combination.     

Activity of quinolones against viridans group streptococci isolated from blood cultures of patients with haematological malignancy

Use of fluoroquinolones for antimicrobial prophylaxis during neutropenia is often cited as a significant predisposing factor for viridans group streptococcus (VGS) bacteraemia. Newer compounds in this class are reputed to have enhanced activity against Gram-positive bacteria, and we determined the minimal inhibitory concentrations (MICs) for ciprofloxacin and three of the newer compounds: trovafloxacin, fleroxacin and clinafloxacin, against 44 isolates of VGS. On a gravimetric basis, clinafloxacin was most active (MIC₉₀ 0.19 mg/l), whereas ciprofloxacin and fleroxacin were the least active (both MIC₉₀ 16 mg/l). Clinafloxacin warrants further study as an agent of prophylaxis against bacterial infection in neutropenic patients.     

Comparative in vitro evaluation of cefonicid, cefazolin, and penicillin against viridans group streptococci isolated from blood.

The in vitro activity of cefonicid against 60 strains of viridans group streptococci isolated from blood of patients with bacteremia and infective endocarditis was compared with those of cefazolin and penicillin. Cefonicid was less active than cefazolin, and both cephalosporins were less active than penicillin. The MIC50 and MIC90 for the strains tested were 0.06 and 1 microgram/ml for penicillin, 0.125 and 8 micrograms/ml for cefazolin, and 4 and 32 micrograms/ml for cefonicid.     

In vitro activity of mersacidin (M87-1551), an investigational peptide antibiotic tested against gram-positive bloodstream isolates.

We measured the in vitro activity of mersacidin (formerly M87-1551) against 183 clinical isolates (vancomycin susceptible) and 12 additional vancomycin-resistant strains of Gram-positive bacteria. The activity for mersacidin increased an average twofold (range, 1.7- to 7.6-fold) in a calcium-enriched medium. The minimum inhibitory concentration (MIC)90 for mersacidin was 8-32 times higher than vancomycin for staphylococci, 4-64 times higher for enterococci, and up to 32 times higher for other organisms tested. The MIC90 for MDL 62873, a comparison compound, was less than or equal to 0.5 micrograms/ml for all species except Staphylococcus haemolyticus (MIC90, 4 micrograms/ml), and it was greater than or equal to 4-fold more active than vancomycin. Against selected vancomycin-resistant strains, mersacidin had MICs greater than or equal to 16 micrograms/ml for enterococci, 4-32 micrograms/ml for Pediococcus, and less than or equal to 2 micrograms/ml for Leuconostoc species. Mersacidin may have some clinical utility in documented infections caused by staphylococci, nonenteric streptococci, Pediococcus, and Leuconostoc.