Pharmacodynamics of an 800-mg dose of telithromycin in patients with community-acquired pneumonia caused by extracellular pathogens.

The pharmacodynamics of telithromycin, a new ketolide antibacterial, was examined in 115 patients with community-acquired pneumonia (CAP). Patients received telithromycin 800 mg qd for 7-10 days. Pharmacokinetic parameters were determined, and exposure was linked to microbiological outcome using logistic regression analysis. A breakpoint for increased probability of microbiological eradication was developed and was found to be the ratio of area under the concentration-time curve (AUC) to minimum inhibitory concentration (MIC) of 3.375. The final logistic regression model of microbiological outcome included body weight and AUC/MIC ratio breakpoint. This model was found in analyses of the entire population and when Streptococcus pneumoniae and Haemophilus influenzae were examined separately. The AUC/MIC ratio target attainment rate is expected to be >99.9% for S. pneumoniae and Moraxella catarrhalis and 93.1% for H. influenzae. This study demonstrated a relationship between telithromycin drug exposure and microbiological outcome. Telithromycin is expected to achieve the drug exposure breakpoint for the majority of isolates causing CAP.

Fluoroquinolones and tuberculosis.

Tuberculosis (TB) remains one of the main causes of morbidity worldwide, and the emergence of multi-drug resistant (MDR) Mycobacterium tuberculosis strains in some parts of the world has become a major concern. The decrease in activity of the major anti-TB drugs, such as isoniazid and rifampicin, is an important threat and alternative therapies are urgently required. The anti-TB activity of the fluoroquinolones has been under investigation since the 1980s. Many are active in vitro but only a few, including ofloxacin, ciprofloxacin, sparfloxacin, levofloxacin and lomefloxacin, have been clinically tested. Fluoroquinolones can be used in co-therapy with the available anti-TB drugs. However, the choice of fluoroquinolone should be based not only on the in vitro activity, but also on the long-term tolerance. Fluoroquinolones are novel anti-TB drugs to be used when a patient is infected with a MDR-TB strain.

Effects of various media on the activity of NXL103 (formerly XRP 2868), a new oral streptogramin, against Haemophilus influenzae.

The activity of NXL103 against 108 strains of Haemophilus influenzae was tested using Haemophilus test media (HTM) obtained from various sources. With the exception of those obtained with stored HTM, MICs did not differ significantly, with MIC(50) and MIC(90) values of 0.5 and 0.5 to 1 microg/ml, respectively, in each medium.

Anti-MRSA agents: under investigation, in the exploratory phase and clinically available.

Staphylococcal infections are difficult to treat due to the rapid emergence of methicillin-resistant staphylococci and, unfortunately, vancomycin-intermediate or -resistant staphylococci. Numerous alternative treatments are urgently required. In this special report, intensive research of new molecules is highlighted--in known antibacterial families and new medicinal chemical entities.

Comparative in vitro activities of XRP 2868, pristinamycin, quinupristin-dalfopristin, vancomycin, daptomycin, linezolid, clarithromycin, telithromycin, clindamycin, and ampicillin against anaerobic gram-positive species, actinomycetes, and lactobacilli.

A comparative study of the in vitro activities of XRP 2868, a new oral streptogramin, against 266 anaerobic gram-positive clinical isolates using the agar dilution method showed that the XRP 2868 MICs for 95% (254 of 266) of isolates were < or =0.5 microg/ml. XRP 2868 MICs for only two strains, one being Clostridium clostridioforme (MIC, 16 microg/ml) and the other being Clostridium difficile (MIC, 32 microg/ml), were >2 microg/ml. Depending on its pharmacokinetics and pharmacodynamics, XRP 2868 has potential for use against infections with gram-positive anaerobes and deserves further clinical evaluation.

In vitro activities of a new lipopeptide, HMR 1043, against susceptible and resistant gram-positive isolates.

The purpose of this study was to compare the activity of HMR 1043 with those of daptomycin and teicoplanin against gram-positive isolates. Susceptibility tests were performed for 52 strains, 26 parental strains, including staphylococcal, streptococcal, enterococcal, and listerial strains, and 26 HMR 1043-resistant mutants obtained from parental strains by using the Szybalski method. Agar dilution and disk diffusion susceptibility tests were performed by the procedures outlined by the NCCLS. HMR 1043 demonstrated good activity against susceptible and resistant gram-positive bacteria. The activity of HMR 1043 in vitro was less influenced by the presence of calcium ions than that of daptomycin. Susceptibility test breakpoints were not defined because of the poor correlation coefficients obtained with the different disks tested.

The AcrAB-TolC pump is involved in macrolide resistance but not in telithromycin efflux in Enterobacter aerogenes and Escherichia coli.

The role of the AcrAB-TolC pump in macrolide and ketolide susceptibility in Escherichia coli and Enterobacter aerogenes was studied. Efflux pump inhibitor restored erythromycin, clarithromycin, and telithromycin susceptibilities to multidrug-resistant isolates. No modification of telithromycin accumulation was detected in E. aerogenes acrAB or tolC derivatives compared to that in the parental strain. Two independent efflux pumps, inhibited by phenylalanine arginine beta-naphthylamide, expel macrolides and telithromycin in E. aerogenes.

Activities of HMR 3787 and RU 64399 compared with those of four other agents against Haemophilus influenzae and Haemophilus parainfluenzae.

Activities of HMR 3787, a new 2-fluoroketolide, and its (des)-fluor derivative, RU 64399, were tested against 111 Haemophilus influenzae and 26 H. parainfluenzae strains and compared with those of telithromycin, erythromycin, azithromycin, and clarithromycin. HMR 3787 and RU 64399 MICs were comparable with those of azithromycin but were less affected by incubation in CO(2). Time-kill studies of 12 strains showed that HMR 3787, RU 64399, and telithromycin were bactericidal against all strains after 24 h at two times the MIC.

Macrolide-resistant Streptococcus pneumoniae and Streptococcus pyogenes in the pediatric population in Germany during 2000-2001.

In a nationwide study in Germany covering 13 clinical microbiology laboratories, a total of 307 Streptococcus pyogenes (mainly pharyngitis) and 333 Streptococcus pneumoniae (respiratory tract infections) strains were collected from outpatients less than 16 years of age. The MICs of penicillin G, amoxicillin, cefotaxime, erythromycin A, clindamycin, levofloxacin, and telithromycin were determined by the microdilution method. In S. pyogenes isolates, resistance rates were as follows: penicillin, 0%; erythromycin A, 13.7%; and levofloxacin, 0%. Telithromycin showed good activity against S. pyogenes isolates (MIC(90) = 0.25 micro g/ml; MIC range, 0.016 to 16 micro g/ml). Three strains were found to be telithromycin-resistant (MIC >/= 4 micro g/ml). Erythromycin-resistant strains were characterized for the underlying resistance genotype, with 40.5% having the efflux type mef(A), 38.1% having the erm(A), and 9.5% having the erm(B) genotypes. emm typing of macrolide-resistant S. pyogenes isolates showed emm types 4 (45.2%), 77 (26.2%), and 12 (11.9%) to be predominant. In S. pneumoniae, resistance rates were as follows: penicillin intermediate, 7.5%; penicillin resistant, 0%; erythromycin A, 17.4%; and levofloxacin, 0%. Telithromycin was highly active against pneumococcal isolates (MIC(90)

Activities of a new oral streptogramin, XRP 2868, compared to those of other agents against Streptococcus pneumoniae and haemophilus species.

MIC methodology was used to test the antibacterial activity of XRP 2868, a new oral combination of two semisynthetic streptogramins, RPR 132552A and RPR 202868, compared to activities of other antibacterial agents against pneumococci, Haemophilus influenzae, and Haemophilus parainfluenzae. For 261 pneumococci, XRP 2868 and pristinamycin MICs were similar, irrespective of penicillin G and erythromycin A susceptibilities (MIC at which 50% of isolates were inhibited [MIC(50)], 0.25 micro g/ml; MIC(90), 0.5 micro g/ml), while quinupristin/dalfopristin had MICs which were 1 to 2 dilutions higher. Single components of both XRP 2868 and quinupristin/dalfopristin had higher MICs. Erythromycin A, azithromycin, clarithromycin, and clindamycin MICs were higher for penicillin G-intermediate and -resistant than -susceptible pneumococci. Against 150 H. influenzae strains, all compounds tested had unimodal MIC distributions. XRP 2868 had an overall MIC(50) of 0.25 micro g/ml and an MIC(90) of 1.0 micro g/ml, with no differences between beta-lactamase-positive, beta-lactamase-negative, and beta-lactamase-negative ampicillin-resistant strains. Of note was the similarly low activity of one of its components, RPR 132552A. Pristinamycin and quinupristin/dalfopristin had MICs of 0.125 to 8.0 micro g/ml; quinupristin alone had MICs of 8.0 to >64.0 micro g/ml, and dalfopristin had MICs of 1.0 to >64.0 micro g/ml. Erythromycin A, azithromycin, and clarithromycin had modal MICs of 4.0, 1.0, and 8.0 micro g/ml, respectively. MICs of all compounds against H. parainfluenzae were 1 to 2 dilutions higher than against H. influenzae. XRP 2868 showed potent activity against pneumococci and Haemophilus strains irrespective of their susceptibility to other agents.

Clonal relatedness of erythromycin-resistant Streptococcus pyogenes isolates in Germany.

In a nationwide study in Germany, a total of 381 Streptococcus pyogenes were collected. Erythromycin A-resistant strains were characterized for the underlying resistance genotype, showing 55.6% had the efflux type mef(A), 31.5% had erm(A), and 13.0% had erm(B). A total of 23 different multilocus sequence types were observed.