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1.  Telithromycin in the treatment of acute bacterial sinusitis, acute exacerbations of chronic bronchitis, and community-acquired pneumonia 
Acute bacterial sinusitis (ABS), acute exacerbations of chronic bronchitis (AECB), and community-acquired pneumonia (CAP) are common conditions and constitute a substantial socioeconomic burden. The ketolides are a new class of antibacterials with a targeted spectrum of antibacterial activity. In vitro, telithromycin is active against common bacterial pathogens that cause upper and lower respiratory tract infections, including some isolates that are resistant to other antibiotic classes. In 2004, telithromycin was the first ketolide antibiotic approved for clinical use by the US Food and Drug Administration for the treatment of adult outpatients with ABS, AECB, and mild-to-moderate CAP. This review discusses the use of telithromycin in the treatment of these infections, providing an overview of its antibacterial activity, pharmacokinetic and pharmacodynamic properties, clinical efficacy, and tolerability–safety, and concludes that telithromycin is an appropriate option for the treatment of community-acquired ABS, AECB, and mild-to-moderate CAP.
PMCID: PMC1661642  PMID: 18360582
telithromycin; respiratory tract infection; ketolide
2.  In Vitro Antibacterial Activity of Modithromycin, a Novel 6,11-Bridged Bicyclolide, against Respiratory Pathogens, Including Macrolide-Resistant Gram-Positive Cocci▿  
The in vitro activities of modithromycin against Gram-positive and -negative respiratory pathogens, including macrolide-resistant cocci with different resistance mechanisms, were compared with those of other macrolide and ketolide agents. MICs were determined by the broth microdilution method. All 595 test strains used in this study were isolated from Japanese medical facilities. The erm (ribosome methylase) and/or mef (efflux pump) gene, which correlated with resistance to erythromycin as well as clarithromycin and azithromycin, was found in 81.8%, 21.3%, and 23.2% of Streptococcus pneumoniae, Streptococcus pyogenes, and methicillin-susceptible Staphylococcus aureus (MSSA) strains, respectively. Modithromycin showed MIC90s of 0.125 μg/ml against these three cocci, including macrolide-resistant strains. In particular, the MIC of modithromycin against ermB-carrying S. pyogenes was ≥32-fold lower than that of telithromycin. The activities of modithromycin as well as telithromycin were little affected by the presence of mefA or mefE in both streptococci. Against Gram-negative pathogens, modithromycin showed MIC90s of 0.5, 8, and 0.031 μg/ml against Moraxella catarrhalis, Haemophilus influenzae, and Legionella spp., respectively. The MICs of modithromycin against M. catarrhalis and H. influenzae were higher than those of telithromycin and azithromycin. However, modithromycin showed the most potent anti-Legionella activity among the macrolide and ketolide agents tested. These results suggested that the bicyclolide agent modithromycin is a novel class of macrolides with improved antibacterial activity against Gram-positive cocci, including telithromycin-resistant streptococci and intracellular Gram-negative bacteria of the Legionella species.
PMCID: PMC3067159  PMID: 21220534
3.  Activity of telithromycin and comparators against bacterial pathogens isolated from 1,336 patients with clinically diagnosed acute sinusitis 
Increasing antimicrobial resistance among the key pathogens responsible for community-acquired respiratory tract infections has the potential to limit the effectiveness of antibiotics available to treat these infections. Since there are regional differences in the susceptibility patterns observed and treatment is frequently empirical, the selection of antibiotic therapy may be challenging. PROTEKT, a global, longitudinal multicentre surveillance study, tracks the activity of telithromycin and comparator antibacterial agents against key respiratory tract pathogens.
In this analysis, we examine the prevalence of antibacterial resistance in 1,336 bacterial pathogens, isolated from adult and paediatric patients clinically diagnosed with acute bacterial sinusitis (ABS).
Results and discussion
In total, 58.0%, 66.1%, and 55.8% of S. pneumoniae isolates were susceptible to penicillin, cefuroxime, and clarithromycin respectively. Combined macrolide resistance and reduced susceptibility to penicillin was present in 200/640 (31.3 %) of S. pneumoniae isolates (128 isolates were resistant to penicillin [MIC >= 2 mg/L], 72 intermediate [MIC 0.12–1 mg/L]) while 99.5% and 95.5% of isolates were susceptible to telithromycin and amoxicillin-clavulanate, respectively. In total, 88.2%, 87.5%, 99.4%, 100%, and 100% of H. influenzae isolates were susceptible to ampicillin, clarithromycin, cefuroxime, telithromycin, and amoxicillin-clavulanate, respectively. In vitro, telithromycin demonstrated the highest activity against M. catarrhalis (MIC50 = 0.06 mg/L, MIC90 = 0.12 mg/L).
The high in vitro activity of against pathogens commonly isolated in ABS, together with a once daily dosing regimen and clinical efficacy with 5-day course of therapy, suggest that telithromycin may play a role in the empiric treatment of ABS.
PMCID: PMC509281  PMID: 15287988
4.  Ketolides in the treatment of community-acquired respiratory tract infections: A review 
The increasing prevalence of resistance to established antibiotics among key respiratory bacterial pathogens highlights a need for new antibacterial agents for the treatment of community-acquired respiratory tract infections (RTIs). Ketolides are a new class of antibiotics specifically developed for the treatment of RTIs.
The aim of this review was to present the current status of treatment of RTIs with ketolides, focusing on telithromycin—the first ketolide to be approved by the US Food and Drug Administration for clinical use.
To gather evidence on the current status of ketolides, a literature search was conducted using MEDLINE (years: 1990–2005; key terms: ketolides, telithromycin, and HMR3647).
Telithromycin shows strong in vitro activity against the major respiratorypathogens, including strains resistant to other antibiotics, as well as the atypical respiratory pathogens. The pharmacokinetic properties of telithromycin are compatible with once-daily dosing. Clinical trials have demonstrated that telithromycin 800 mg QD for 5 to 10 days is effective in the treatment of acute bacterial sinusitis, acute bacterial exacerbations of chronic bronchitis, and mild to moderate community-acquired pneumonia. Overall, telithromycin is well tolerated by patients. Drug-drug interactions are similar to those reported for macrolides.
Evidence to date indicates that telithromycin is an effective andwell-tolerated empiric treatment for community-acquired RTIs.
PMCID: PMC3964523  PMID: 24672119
respiratory tract infections; antibiotics; ketolides; telithromycin
5.  In Vitro Activities of Novel 2-Fluoro-Naphthyridine-Containing Ketolides 
In vitro activities of erythromycin A, telithromycin, and two investigational ketolides, JNJ-17155437 and JNJ-17155528, were evaluated against clinical bacterial strains, including selected common respiratory tract pathogens. Against 46 macrolide-susceptible and -resistant Streptococcus pneumoniae strains, the MIC90 (MIC at which 90% of the isolates tested were inhibited) of the investigational ketolides was 0.25 μg/ml, twofold lower than that of telithromycin and at least 64-fold lower than that of erythromycin A. Against erm(B)-containing pneumococci, the MIC90 of all the ketolides was 0.06 μg/ml. The MIC90 of the investigational ketolides against mef(A)-containing pneumococci or pneumococci with both mef(A) and erm(B) was 0.25 μg/ml, two-and fourfold lower, respectively, than that of telithromycin. In contrast, the MICs of the investigational ketolides against macrolide-resistant S. pneumoniae strains with ribosomal mutations were similar to or, in some cases, as much as eightfold higher than those of telithromycin. Against Haemophilus influenzae, MICs of all the ketolides were ≤2 μg/ml. Against three Moraxella catarrhalis isolates, the MIC of the ketolides was 0.25 μg/ml. The ketolides inhibited in vitro protein synthesis, with 50% inhibitory concentrations ranging from 0.23 to 0.27 μM. In time-kill studies against macrolide-susceptible and erm- or mef-containing pneumococci, the ketolides were bacteriostatic to slowly bactericidal, with 24-h log10 decreases ranging from 2.0 to 4.1 CFU. Intervals of postantibiotic effects for the ketolides against macrolide-susceptible and -resistant S. pneumoniae were 3.0 to 8.1 h.
PMCID: PMC538878  PMID: 15616310
6.  Efficacy and safety of telithromycin 800 mg once daily for 7 days in community-acquired pneumonia: an open-label, multicenter study 
Community-acquired pneumonia (CAP) remains a major cause of morbidity and mortality throughout the world. Telithromycin (a new ketolide) has shown good in vitro activity against the key causative pathogens of CAP, including S pneumoniae resistant to penicillin and/or macrolides.
The efficacy and safety of telithromycin 800 mg orally once daily for 7 days in the treatment of CAP were assessed in an open-label, multicenter study of 442 adults.
Of 149 microbiologically evaluable patients, 57 (9 bacteremic) had Streptococcus pneumoniae. Of the 57 S pneumoniae pathogens isolated in these patients, 9 (2 bacteremic) were penicillin- or erythromycin-resistant; all 57 were susceptible to telithromycin and were eradicated. Other pathogens and their eradication rates were: Haemophilus influenzae (96%), Moraxella catarrhalis (100%), Staphylococcus aureus (80%), and Legionella spp. (100%). The overall bacteriologic eradication rate was 91.9%. Of the 357 clinically evaluable patients, clinical cure was achieved in 332 (93%). In the 430 patients evaluable for safety, the most common drug-related adverse events were diarrhea (8.1%) and nausea (5.8%).
Telithromycin 800 mg once daily for 7 days is an effective and well-tolerated oral monotherapy and offers a new treatment option for CAP patients, including those with resistant S pneumoniae.
PMCID: PMC1177948  PMID: 15927060
7.  In Vitro Activities of Telithromycin and 10 Oral Agents against Aerobic and Anaerobic Pathogens Isolated from Antral Puncture Specimens from Patients with Sinusitis 
A study of the comparative in vitro activity of telithromycin, a new ketolide, against 155 aerobic and 171 anaerobic antral sinus puncture isolates showed it to be active against a broad range of sinus pathogens. All pneumococci, including erythromycin-resistant strains, were susceptible to telithromycin at ≤0.5 μg/ml; all Haemophilus influenzae and Eikenella corrodens strains were inhibited by ≤4 μg of telithromycin/ml; all Moraxella spp. and beta-lactamase-producing Prevotella species strains were inhibited by ≤0.25 and 0.5 μg of telithromycin/ml, respectively. Among all anaerobes tested, 94% (160 of 171 strains) were susceptible to ≤4 μg of telithromycin/ml; however, 8 of 17 (47%) Fusobacterium strains, 2 Veillonella strains, and 1 Peptostreptococcus micros strain required >4 μg of telithromycin/ml for inhibition. Telithromycin may offer a therapeutic alternative for sinus infections, including those due to erythromycin-resistant pneumococci.
PMCID: PMC155841  PMID: 12760875
8.  Results from the Solithromycin International Surveillance Program (2014) 
Solithromycin, a fourth-generation macrolide (a fluoroketolide with enhanced activity against macrolide-resistant bacteria due to interaction with three ribosomal sites) and the first fluoroketolide, was tested against a 2014 collection of 6,115 isolates, including Streptococcus pneumoniae (1,713 isolates), Haemophilus influenzae (1,308), Moraxella catarrhalis (577), Staphylococcus aureus (1,024), and beta-hemolytic streptococci (1,493), by reference broth microdilution methods. The geographic samples included 2,748 isolates from the United States, 2,536 from Europe, 386 from Latin America, and 445 from the Asia-Pacific region. Solithromycin was observed to be very active against S. pneumoniae (MIC50/90, 0.008/0.12 μg/ml), demonstrating 2-fold greater activity than telithromycin (MIC50/90, 0.015/0.25 μg/ml) and 16- to >256-fold greater activity than azithromycin (MIC50/90, 0.12/>32 μg/ml), with all strains being inhibited at a solithromycin MIC of ≤1 μg/ml. Against H. influenzae, solithromycin showed potency identical to that of telithromycin (MIC50/90, 1/2 μg/ml), and both of these compounds were 2-fold less active than azithromycin (MIC50/90, 0.5/1 μg/ml). All but one of the M. catarrhalis isolates were inhibited by solithromycin at ≤0.25 μg/ml. Solithromycin inhibited 85.3% of S. aureus isolates at ≤1 μg/ml, and its activity was lower against methicillin-resistant (MIC50/90, 0.06/>32 μg/ml) than against methicillin-susceptible (MIC50/90, 0.06/0.06 μg/ml) isolates. Little variation in solithromycin activity was observed by geographic region for the species tested. Solithromycin was very active against beta-hemolytic streptococci (MIC50/90, 0.015/0.03 μg/ml), and all isolates were inhibited at MIC values of ≤0.5 μg/ml. In conclusion, solithromycin demonstrated potent activity against global and contemporary (2014) pathogens that represent the major causes of community-acquired bacterial pneumonia. These data support the continued clinical development of solithromycin for the treatment of this important indication.
PMCID: PMC4879362  PMID: 27044551
9.  In vitro Activities of Oral Cephem and Telithromycin Against Clinical Isolates of Major Respiratory Pathogens in Japan 
The in vitro antibacterial activities of oral cephem antibiotics and ketolide telithromycin against major respiratory pathogens possessing β-lactam-resistant mutations (within the pbp gene) and/or macrolide-resistant genes (erm and mef) were examined in clinical isolates collected at 66 institutes in all over the Japan between 2002 and 2003. Telithromycin showed the strongest antibacterial activity against methicillin-susceptible Staphylococcus aureus strains with and without macrolide-resistant genes, such as ermA or ermC gene. All the cephem antibiotics showed potent antibacterial activity against Streptococcus pyogenes, with minimum inhibitory concentrations (MICs) of 0.015 mg/L or lower. Cefdinir had a much higher MIC90 against genotypic penicillin-resistant Streptococcus pneumoniae (gPRSP) than cefditoren and cefcapene (8 mg/L cefdinir vs. 1 mg/L cefditoren and cefcapene). The majority of gPRSP harbored either ermB or mefA, and the antibacterial activity of telithromycin against these strains was decreased however some susceptibility was still sustained. Cefditoren exerted the strongest antibacterial activity against β-lactamase-negative ampicillin-resistant Haemophilus influenzae, with an MIC90 of 0.5 mg/L. These results underline the importance of checking the susceptibility and selecting an appropriate antibiotic against target pathogens.
PMCID: PMC2693563  PMID: 17297246
cefditoren; telithromycin; Microbial Sensitivity Tests; Minimum Inhibitory Concentration; beta-Lactams
10.  In vitro activity of telithromycin against Haemophilus influenzae at epithelial lining fluid concentrations 
BMC Microbiology  2008;8:23.
Haemophilus influenzae is one of the main aetiological agents of community-acquired respiratory tract infections. The primary aim of this study was to evaluate the antibacterial activity of telithromycin against H. influenzae clinical isolates showing different pattern of resistance in comparison with azithromycin and clarithromycin at 1/4 ×, 1/2 ×, 1 ×, 2 ×, 4 × minimum inhibitory concentration (MIC) and to peak concentrations in epithelial lining fluid (ELF). The secondary aim was to determine the influence of CO2 enriched atmosphere on bacterial susceptibility.
Telithromycin showed high activity against H. influenzae, including strains susceptible to β-lactams (n = 200), β-lactamase producer (n = 50) and β-lactamase negative ampicillin resistant (BLNAR) (n = 10), with MIC from ≤0.03 to 4 mg/L, and MIC50/MIC90 of 1/2 mg/L with susceptibility rate of 100%, and minimum bactericidal concentrations (MBC) from 2 to 4-fold higher than the MIC. Azithromycin was the most active tested macrolide (range: 0.25 – 4 mg/L; MIC50/MIC90: 1/2 mg/L), comparable to telithromycin, while clarithromycin showed the highest MICs and MBCs (range: 0.25 – 8 mg/L; MIC50/MIC90: 2/8 mg/L). In time-kill studies, telithromycin showed a bactericidal activity at the higher concentrations (4 – 2 × MIC and ELF) against all the strains, being complete after 12 – 24 hours from drug exposition. At MIC concentrations, at ambient air, bactericidal activity of telithromycin and azithromycin was quite similar at 12 hours, and better than that of clarithromycin. Besides, telithromycin and clarithromycin at ELF concentrations were bactericidal after 12 hours of incubation for most strains, while 24 hours were needed to azithromycin to be bactericidal. Incubation in CO2 significantly influenced the MICs and MBCs, and only slightly the in vitro killing curves.
Telithromycin showed an in-vitro potency against H. influenzae comparable to azithromycin, with an in-vitro killing rate more rapid and superior to clarithromycin at 2X-MIC against β-lactamase producers and BLNAR strains, and to azithromycin at ELF concentrations against β-lactamase negative strains. Against all strains, MICs and MBCs were lower in the absence of CO2 for the tested antibiotics, showing an adverse effect of incubation in a CO2 environment. The in-vitro potency together with the tissue concentrations of the antimicrobial, should be considered in predicting efficacy.
PMCID: PMC2270277  PMID: 18230154
11.  Comparison of In Vitro Activities of ABT-773 and Telithromycin against Macrolide-Susceptible and -Resistant Streptococci and Staphylococci 
The activity of a new ketolide, ABT-773, was compared to the activity of the ketolide telithromycin (HMR-3647) against over 600 gram-positive clinical isolates, including 356 Streptococcus pneumoniae, 167 Staphylococcus aureus, and 136 Streptococcus pyogenes isolates. Macrolide-susceptible isolates as well as macrolide-resistant isolates with ribosomal methylase (Erm), macrolide efflux (Mef), and ribosomal mutations were tested using the NCCLS reference broth microdilution method. Both compounds were extremely active against macrolide-susceptible isolates, with the minimum inhibitory concentrations at which 90% of the isolates tested were inhibited (MIC90s) for susceptible streptococci and staphylococci ranging from 0.002 to 0.03 μg/ml for ABT-773 and 0.008 to 0.06 μg/ml for telithromycin. ABT-773 had increased activities against macrolide-resistant S. pneumoniae (Erm MIC90, 0.015 μg/ml; Mef MIC90, 0.12 μg/ml) compared to those of telithromycin (Erm MIC90, 0.12 μg/ml; Mef MIC90, 1 μg/ml). Both compounds were active against strains with rRNA or ribosomal protein mutations (MIC90, 0.12 μg/ml). ABT-773 was also more active against macrolide-resistant S. pyogenes (ABT-773 Erm MIC90, 0.5 μg/ml; ABT-773 Mef MIC90, 0.12 μg/ml; telithromycin Erm MIC90, >8 μg/ml; telithromycin Mef MIC90, 1.0 μg/ml). Both compounds lacked activity against constitutive macrolide-resistant Staphylococcus aureus but had good activities against inducibly resistant Staphylococcus aureus (ABT-773 MIC90, 0.06 μg/ml; telithromycin MIC90, 0.5 μg/ml). ABT-773 has superior activity against macrolide-resistant streptococci compared to that of telithromycin.
PMCID: PMC127460  PMID: 11850262
12.  Pharmacodynamic Profile of Telithromycin against Macrolide- and Fluoroquinolone-Resistant Streptococcus pneumoniae in a Neutropenic Mouse Thigh Model 
The new ketolide telithromycin has potent in vitro activity against Streptococcus pneumoniae, including strains resistant to penicillin, macrolides, and fluoroquinolones. The aim of the present study was to define the pharmacodynamic profile of telithromycin against S. pneumoniae strains with various resistance profiles in an in vivo system. Ten S. pneumoniae strains were studied; seven exhibited penicillin resistance, six demonstrated macrolide resistance, and two exhibited gatifloxacin resistance. The telithromycin MICs for all isolates were ≤0.5 μg/ml. Using the murine thigh infection model, CD-1/ICR mice were rendered neutropenic and were then inoculated with 105 to 106 CFU of S. pneumoniae per thigh. Telithromycin was administered orally at doses ranging from 25 to 800 mg/kg of body weight/day, with the doses administered one, two, three, or four times a day. The activity of telithromycin was assessed by determination of the change in the bacterial density in thigh tissue after 24 h of treatment for each treatment group and the untreated controls. Pharmacokinetic studies of telithromycin were conducted in infected, neutropenic animals. The levels of protein binding by telithromycin in mice ranged from 70 to 95% over the observed range of pharmacokinetic concentrations. By using either the total or the free concentrations of telithromycin, the area under the concentration-time curve (AUC)/MIC ratio was a strong determinant of the response against S. pneumoniae, regardless of the phenotypic resistance profile. The maximal efficacy (the 95% effective dose) against this cohort of S. pneumoniae strains and bacterial inhibition (stasis) of telithromycin were predicted by ratios of the AUC for the free drug concentration/MIC of approximately 1,000 and 200, respectively.
PMCID: PMC538883  PMID: 15616295
13.  Pharmacodynamics of Telithromycin In Vitro against Respiratory Tract Pathogens 
Telithromycin (HMR 3647) is a new ketolide that belongs to a new class of semisynthetic 14-membered-ring macrolides which have expanded activity against multidrug-resistant gram-positive bacteria. The aim of the present study was to investigate different basic pharmacodynamic properties of this new compound. The following studies of telithromycin were performed: (i) studies of the rate and extent of killing of respiratory tract pathogens with different susceptibilities to erythromycin and penicillin exposed to a fixed concentration that corresponds to a dose of 800 mg in humans, (ii) studies of the rate and extent of killing of telithromycin at five different concentrations, (iii) studies of the rate and extent of killing of the same pathogens at three different inocula, (iv) studies of the postantibiotic effect and the postantibiotic sub-MIC effect of telithromycin, and (v) determination of the rate and extent of killing of telithromycin in an in vitro kinetic model. In conclusion, telithromycin exerted an extremely fast killing of all strains of Streptococcus pneumoniae both with static concentrations and in the in vitro kinetic model. A slower killing of the strains of Streptococcus pyogenes was noted, with regrowth in the kinetic model of a macrolide-lincosamide-streptogramin B-inducible strain. The strains of Haemophilus influenzae were not killed at all at a concentration of 0.6 mg/liter due to high MICs. A time-dependent killing was seen for all strains. No inoculum effect was seen for the strains of S. pneumoniae, with a 99.9% reduction in the numbers of CFU for all inocula at both 8 h and 24 h. The killing of the strains of S. pyogenes was reduced by 1 log10 CFU at 8 h and 2 to 3 log10 CFU at 24 h when the two lower inocula were used but not at all at 8 and 24 h when the highest inoculum was used. For both of the H. influenzae strains there was an inoculum effect, with 1 to 2 log10 CFU less killing for the inoculum of 108 CFU/ml in comparison to that for the inoculum of 106 CFU/ml. Overall, telithromycin exhibited long postantibiotic effects and postantibiotic sub-MIC effects for all strains investigated.
PMCID: PMC90234  PMID: 11120939
14.  CEM-101 Activity against Gram-Positive Organisms▿  
The in vitro activity of CEM-101, a new fluoroketolide, was determined against Gram-positive organisms with various macrolide susceptibility profiles. Experiments for determination of the MICs and minimum bactericidal concentrations (MBCs), timed killing, single-step and multistep mutation rates, the erythromycin induction of resistance, postantibiotic effect (PAE), and drug interactions were performed for CEM-101; and the results were compared to those obtained with telithromycin, macrolides, and lincosamides. The MBCs of CEM-101 remained lower overall than those of telithromycin, and CEM-101 displayed a 2-fold greater potency than the ketolide. Timed-killing curve testing showed that CEM-101 had greater bactericidal activity than telithromycin (a ≥3-log10-CFU/ml decrease in the initial inoculum at 24 h) against the staphylococcal isolates tested. The propensity of CEM-101 to cause resistance was low, as determined from the rates of resistance determined in single-step mutational studies (<10−8 or 10−9). In multipassaging studies, mutants of two strains (both of which were USA300 isolates) resistant to CEM-101 emerged. That number was comparable to the number resistant to clindamycin but less than the number resistant to telithromycin. Erythromycin induced CEM-101 resistance in Staphylococcus aureus and Streptococcus pneumoniae, similar to telithromycin; however, in seven of eight beta-hemolytic streptococci, CEM-101 resistance induction was not observed. CEM-101 showed a significant concentration- and exposure-dependent PAE against the strains tested, with the values ranging from 2.3 to 6.1 h for Gram-positive organisms (these times were longer than those for telithromycin). No antagonism was found in synergy analyses, with enhanced inhibition being most noted for combinations with CEM-101 and ceftriaxone, gentamicin, and trimethoprim-sulfamethoxazole. Overall, this new antimicrobial agent (CEM-101) showed good antimicrobial characteristics compared with those of the agents in its class and exhibited measured parameter values similar or superior to those of utilized comparators, indicating that CEM-101 warrants further clinical evaluation.
PMCID: PMC2863667  PMID: 20176910
15.  Mechanisms, molecular and sero-epidemiology of antimicrobial resistance in bacterial respiratory pathogens isolated from Japanese children 
The clinical management of community-acquired respiratory tract infections (RTIs) is complicated by the increasing worldwide prevalence of antibacterial resistance, in particular, β-lactam and macrolide resistance, among the most common causative bacterial pathogens. This study aimed to determine the mechanisms and molecular- and sero-epidemiology of antibacterial resistance among the key paediatric respiratory pathogens in Japan.
Isolates were collected at 18 centres in Japan during 2002 and 2003 from children with RTIs as part of the PROTEKT surveillance programme. A proportion of Haemophilus influenzae isolates was subjected to sequencing analysis of the ftsI gene; phylogenetic relatedness was assessed using multilocus sequence typing. Streptococcus pneumoniae isolates were screened for macrolide-resistance genotype by polymerase chain reaction and serotyped using the capsular swelling method. Susceptibility of isolates to selected antibacterials was performed using CLSI methodology.
Results and Discussion
Of the 557 H. influenzae isolates collected, 30 (5.4%) were β-lactamase-positive [BL+], 115 (20.6%) were BL-nonproducing ampicillin-resistant (BLNAR; MIC ≥ 4 mg/L) and 79 (14.2%) were BL-nonproducing ampicillin-intermediate (BLNAI; MIC 2 mg/L). Dabernat Group III penicillin binding protein 3 (PBP3) amino acid substitutions in the ftsI gene were closely correlated with BLNAR status but phylogenetic analysis indicated marked clonal diversity. PBP mutations were also found among BL+ and BL-nonproducing ampicillin-sensitive isolates. Of the antibacterials tested, azithromycin and telithromycin were the most active against H. influenzae (100% and 99.3% susceptibility, respectively). A large proportion (75.2%) of the 468 S. pneumoniae isolates exhibited macrolide resistance (erythromycin MIC ≥ 1 mg/L); erm(B) was the most common macrolide resistance genotype (58.8%), followed by mef(A) (37.2%). The most common pneumococcal serotypes were 6B (19.7%), 19F (13.7%), 23F (13.5%) and 6A (12.8%). Telithromycin and amoxicillin-clavulanate were the most active antibacterials against S. pneumoniae (99.8% and 99.6% susceptibility, respectively).
Approximately one-third of H. influenzae isolates from paediatric patients in Japan are BLNAI/BLNAR, mainly as a result of clonally diverse PBP3 mutations. Together with the continued high prevalence of pneumococcal macrolide resistance, these results may have implications for the clinical management of paediatric RTIs in Japan.
PMCID: PMC2020463  PMID: 17697316
16.  In Vivo Efficacy of the New Ketolide Telithromycin (HMR 3647) in Murine Infection Models 
We compared the oral antibacterial activities of telithromycin (HMR 3647), a new ketolide drug, in different infections induced in mice by Staphylococcus aureus, Streptococcus pneumoniae, streptococci, enterococci, and Haemophilus influenzae with those of various macrolides and pristinamycin. Unlike all other comparators, telithromycin displayed a high therapeutic activity, particularly in septicemia induced by erythromycin A-resistant pathogens, where the ketolide was the only active compound, displaying effective doses between 3 and 26 mg/kg of body weight. Against H. influenzae, telithromycin was the most effective compound. Telithromycin displayed bacteriostatic behavior against S. pneumoniae and H. influenzae. The ketolide was also active against thigh muscle infection induced by S. aureus. The pharmacokinetic properties of telithromycin accounted for its outstanding well-balanced oral in vivo efficacy against both gram-positive cocci, whatever their phenotype of resistance, and H. influenzae.
PMCID: PMC90532  PMID: 11353612
17.  Trends in antibacterial resistance among Streptococcus pneumoniae isolated in the USA: update from PROTEKT US Years 1–4 
The increasing prevalence of resistance to established antibiotics among key bacterial respiratory tract pathogens, such as Streptococcus pneumoniae, is a major healthcare problem in the USA. The PROTEKT US study is a longitudinal surveillance study designed to monitor the susceptibility of key respiratory tract pathogens in the USA to a range of commonly used antimicrobials. Here, we assess the geographic and temporal trends in antibacterial resistance of S. pneumoniae isolates from patients with community-acquired respiratory tract infections collected between Year 1 (2000–2001) and Year 4 (2003–2004) of PROTEKT US.
Antibacterial minimum inhibitory concentrations were determined centrally using the Clinical and Laboratory Standards Institute (CLSI) broth microdilution method; susceptibility was defined according to CLSI interpretive criteria. Macrolide resistance genotypes were determined by polymerase chain reaction.
A total of 39,495 S. pneumoniae isolates were collected during 2000–2004. The percentage of isolates resistant to erythromycin, penicillin, levofloxacin, and telithromycin were 29.3%, 21.2%, 0.9%, and 0.02%, respectively, over the 4 years, with marked regional variability. The proportion of isolates exhibiting multidrug resistance (includes isolates known as penicillin-resistant S. pneumoniae and isolates resistant to ≥ 2 of the following antibiotics: penicillin; second-generation cephalosporins, e.g. cefuroxime; macrolides; tetracyclines; and trimethoprim-sulfamethoxazole) remained stable at ~30% over the study period. Overall mef(A) was the most common macrolide resistance mechanism. The proportion of mef(A) isolates decreased from 68.8% to 62.3% between Year 1 and Year 4, while the percentage of isolates carrying both erm(B) and mef(A) increased from 9.7% to 18.4%. Over 99% of the erm(B)+mef(A)-positive isolates collected over Years 1–4 exhibited multidrug resistance. Higher than previously reported levels of macrolide resistance were found for mef(A)-positive isolates.
Over the first 4 years of PROTEKT US, penicillin and erythromycin resistance among pneumococcal isolates has remained high. Although macrolide resistance rates have stabilized, the prevalence of clonal isolates, with a combined erm(B) and mef(A) genotype together with high-level macrolide and multidrug resistance, is increasing, and their spread may have serious health implications. Telithromycin and levofloxacin both showed potent in vitro activity against S. pneumoniae isolates irrespective of macrolide resistance genotype.
PMCID: PMC2262084  PMID: 18190701
18.  Pharmacodynamic Activity of Telithromycin at Simulated Clinically Achievable Free-Drug Concentrations in Serum and Epithelial Lining Fluid against Efflux (mefE)-Producing Macrolide- Resistant Streptococcus pneumoniae for Which Telithromycin MICs Vary 
The present study, using an in vitro model, assessed telithromycin pharmacodynamic activity at simulated clinically achievable free-drug concentrations in serum (S) and epithelial lining fluid (ELF) against efflux (mefE)-producing macrolide-resistant Streptococcus pneumoniae. Two macrolide-susceptible (PCR negative for both mefE and ermB) and 11 efflux-producing macrolide-resistant [PCR-positive for mefE and negative for ermB) S. pneumoniae strains with various telithromycin MICs (0.015 to 1 μg/ml) were tested. The steady-state pharmacokinetics of telithromycin were modeled, simulating a dosage of 800 mg orally once daily administered at time 0 and at 24 h (free-drug maximum concentration [Cmax] in serum, 0.7 μg/ml; half-life [t1/2], 10 h; free-drug Cmax in ELF, 6.0 μg/ml; t1/2, 10 h). Starting inocula were 106 CFU/ml in Mueller-Hinton Broth with 2% lysed horse blood. Sampling at 0, 2, 4, 6, 12, 24, and 48 h assessed the extent of bacterial killing (decrease in log10 CFU/ml versus initial inoculum). Free-telithromycin concentrations in serum achieved in the model were Cmax 0.9 ± 0.08 μg/ml, area under the curve to MIC (AUC0-24 h) 6.4 ± 1.5 μg · h/ml, and t1/2 of 10.6 ± 0.6 h. Telithromycin-free ELF concentrations achieved in the model were Cmax 6.6 ± 0.8 μg/ml, AUC0-24 h 45.5 ± 5.5 μg · h/ml, and t1/2 of 10.5 ± 1.7 h. Free-telithromycin S and ELF concentrations rapidly eradicated efflux-producing macrolide-resistant S. pneumoniae with telithromycin MICs up to and including 0.25 μg/ml and 1 μg/ml, respectively. Free-telithromycin S and ELF concentrations simulating Cmax/MIC ≥ 3.5 and AUC0-24 h/MIC ≥ 25 completely eradicated (≥4 log10 killing) macrolide-resistant S. pneumoniae at 24 and 48 h. Free-telithromycin concentrations in serum simulating Cmax/MIC ≥ 1.8 and AUC0-24 h/MIC ≥ 12.5 were bacteriostatic (0.1 to 0.2 log10 killing) against macrolide-resistant S. pneumoniae at 24 and 48 h. In conclusion, free-telithromycin concentrations in serum and ELF simulating Cmax/MIC ≥ 3.5 and AUC0-24 h/MIC ≥ 25 completely eradicated (≥4 log10 killing) macrolide-resistant S. pneumoniae at 24 and 48 h.
PMCID: PMC1087669  PMID: 15855517
19.  Greatest International ANtiinfective Trial (GIANT) with moxifloxacin in the treatment of acute exacerbation of chronic bronchitis: subanalysis of Chinese data of a global, multicenter, noninterventional study 
Clinical Epidemiology  2010;2:15-21.
Background and objective:
A single infective acute exacerbation of chronic bronchitis (AECB) has a sustained effect on health status. Although a number of clinical investigations have demonstrated the efficacy of antibiotics in AECB, increased bacterial resistance has caused concern about the efficacy of currently available antibiotic therapies. This subanalysis of a global noninterventional study aimed to evaluate the impact of AECB on the patient and the community and the effectiveness and safety of a treatment with moxifloxacin (MXF) tablets in daily life clinical practice in China.
This prospective, noninterventional, noncontrolled, multicenter observational study, which started in China in April 2004 and ended in February 2007, was part of the global GIANT study. Patients with a diagnosis of mild to severe AECB were treated with MXF tablets 400 mg for a period at the physician’s discretion. The observation period for each patient covered a complete treatment period with MXF. For each patient, the physician documented data at an initial visit (baseline) and at least one follow-up visit. Data were collected on demography, diagnosis of infection, pretreatment, concomitant diseases and medications, MXF therapy, course of symptoms during investigations, and final assessment of therapy with respect to MXF.
In the Chinese subset of the GIANT study, a total of 11,377 patients were included in the intention-to-treat/safety population. At the end of the initial treatment period, improvement and recovery from infection was observed for 98.6% (n = 11,217/11,377) and 92.6% (n = 10,540/11,377) of all patients. After 1 week of treatment, 76.3% (n = 8681/11,377) of patients had recovered. Median time until improvement and recovery was 3.0 and 6.0 days, respectively. Correspondingly, in 95.8% (n = 10,903/11,377) of all patients, overall effectiveness during the initial treatment period with MXF was assessed as “very good” or “good”. Compared with the last AECB, the number of days with impact on daily-life activities and the number of nights with sleep disturbances decreased from 3.0 to 2.0 (median) and from 2.0 to 1.0 (median), respectively. In general, MXF treatment was very well tolerated, with physician’s overall assessment of tolerability as “good” or “very good” in 95.2% (n = 10,834/11,377) of patients. The incidence rate of adverse events and adverse drug reactions was 0.82% (n = 93) and 0.67% (n = 76), respectively. The most frequent adverse events were gastrointestinal disorders such as nausea (0.31%, n = 35) and vomiting (0.19%, n = 22), which were mostly drug-related. One individual serious adverse event (dyspnea) occurred during the observation period, which was assessed as drug-related.
MXF was effective and well tolerated in patients suffering from AECB. The fast speed of the drug’s onset of action was associated with rapid improvement of clinical parameters.
PMCID: PMC2943190  PMID: 20865098
China; moxifloxacin; chronic bronchitis; acute exacerbation; GIANT
20.  Impact of Ribosomal Modification on the Binding of the Antibiotic Telithromycin Using a Combined Grand Canonical Monte Carlo/Molecular Dynamics Simulation Approach 
PLoS Computational Biology  2013;9(6):e1003113.
Resistance to macrolide antibiotics is conferred by mutation of A2058 to G or methylation by Erm methyltransferases of the exocyclic N6 of A2058 (E. coli numbering) that forms the macrolide binding site in the 50S subunit of the ribosome. Ketolides such as telithromycin mitigate A2058G resistance yet remain susceptible to Erm-based resistance. Molecular details associated with macrolide resistance due to the A2058G mutation and methylation at N6 of A2058 by Erm methyltransferases were investigated using empirical force field-based simulations. To address the buried nature of the macrolide binding site, the number of waters within the pocket was allowed to fluctuate via the use of a Grand Canonical Monte Carlo (GCMC) methodology. The GCMC water insertion/deletion steps were alternated with Molecular Dynamics (MD) simulations to allow for relaxation of the entire system. From this GCMC/MD approach information on the interactions between telithromycin and the 50S ribosome was obtained. In the wild-type (WT) ribosome, the 2′-OH to A2058 N1 hydrogen bond samples short distances with a higher probability, while the effectiveness of telithromycin against the A2058G mutation is explained by a rearrangement of the hydrogen bonding pattern of the 2′-OH to 2058 that maintains the overall antibiotic-ribosome interactions. In both the WT and A2058G mutation there is significant flexibility in telithromycin's imidazole-pyridine side chain (ARM), indicating that entropic effects contribute to the binding affinity. Methylated ribosomes show lower sampling of short 2′-OH to 2058 distances and also demonstrate enhanced G2057-A2058 stacking leading to disrupted A752-U2609 Watson-Crick (WC) interactions as well as hydrogen bonding between telithromycin's ARM and U2609. This information will be of utility in the rational design of novel macrolide analogs with improved activity against methylated A2058 ribosomes.
Author Summary
Bacterial resistance to antibiotics is a serious public health problem that requires the continuous development of new antibiotics. Bacteria acquire resistance to macrolide antibiotics by (1) effluxing the drug from the cell, (2) modifying the drug, or (3) modifying the drug target (i.e., the 50S subunit of the ribosome) to abrogate or completely abolish binding. While newer antibiotics are able to avoid the first two mechanisms, they remain unable to overcome resistance due to ribosomal modification, particularly due to methyltransferase (i.e., erm) enzymes. We have applied computer-aided drug design methods designed explicitly for studies of the ribosome to better understand the relationship between modification of the ribosome by erms and the binding of telithromycin, a 3rd generation ketolide antibiotic derived from erythromycin. While we confirm that ribosomal modification leads to decreased binding due to disruption of key interactions with the drug, we find these modifications effect a structural rearrangement of the entire region of the ribosome responsible for binding macrolide antibiotics. This information will be useful in the design of novel antibiotics that are effective against resistant bacteria possessing modified ribosomes.
PMCID: PMC3681621  PMID: 23785274
21.  Telithromycin: a novel agent for the treatment of community-acquired upper respiratory infections 
The ketolides are a new subclass of macrolides, and telithromycin is the first of these agents to be approved. Modifications to the basic macrolide structure result in enhanced activity against penicillin- and erythromycin resistant respiratory pathogens. It is therefore an option in the treatment of mild to moderate community-acquired respiratory infections, such as pneumonia, acute exacerbations of chronic bronchitis, pharyngitis/tonsillitis, and sinusitis. Telithromycin also offers the advantages of once-daily dosing and a shorter course of therapy in certain infections. Comparative clinical trials, although limited and involving only a small number of resistant organisms, showed the equivalence of telithromycin to existing therapies, although telithromycin generally had a higher frequency of mild to moderate gastrointestinal adverse effects. Further clinical and safety data, especially in patients with resistant organisms, are needed.
PMCID: PMC1200691  PMID: 16200139
22.  Antimicrobial Resistance in Haemophilus influenzae and Moraxella catarrhalis Respiratory Tract Isolates: Results of the Canadian Respiratory Organism Susceptibility Study, 1997 to 2002 
A total of 7,566 unique patient isolates of Haemophilus influenzae and 2,314 unique patient isolates of Moraxella catarrhalis were collected between October 1997 and June 2002 from 25 medical centers in 9 of the 10 Canadian provinces. Among the 7,566 H. influenzae isolates, 22.5% produced β-lactamase, while 92.4% of the 2,314 M. catarrhalis isolates produced β-lactamase. The incidence of β-lactamase-producing H. influenzae isolates decreased significantly over the 5-year study period, from 24.2% in 1997-1998 to 18.6% in 2001-2002 (P < 0.01). The incidence of β-lactamase-producing M. catarrhalis isolates did not change over the study period. The overall rates of resistance to amoxicillin and amoxicillin-clavulanate for H. influenzae were 19.3 and 0.1%, respectively. The rank order of cephalosporin activity based on the MICs at which 90% of isolates were inhibited (MIC90s) was cefotaxime > cefixime > cefuroxime > cefprozil > cefaclor. On the basis of the MICs, azithromycin was more active than clarithromycin (14-OH clarithromycin was not tested); however, on the basis of the NCCLS breakpoints, resistance rates were 2.1 and 1.6%, respectively. Rates of resistance to other agents were as follows: doxycycline, 1.5%; trimethoprim-sulfamethoxazole, 14.2%; and chloramphenicol, 0.2%. All fluoroquinolones tested, including the investigational fluoroquinolones BMS284756 (garenoxacin) and ABT-492, displayed potent activities against H. influenzae, with MIC90s of ≤0.03 μg/ml. The MIC90s of the investigational ketolides telithromycin and ABT-773 were 2 and 4 μg/ml, respectively, and the MIC90 of the investigational glycylcycline GAR-936 (tigecycline) was 4 μg/ml. Among the M. catarrhalis isolates tested, the resistance rates derived by using the NCCLS breakpoint criteria for H. influenzae were <1% for all antibiotics tested except trimethoprim-sulfamethoxazole (1.5%). In summary, the incidence of β-lactamase-positive H. influenzae strains in Canada is decreasing (18.6% in 2001-2002), while the incidence of β-lactamase-positive M. catarrhalis strains has remained constant (90.0% in 2001-2002).
PMCID: PMC155833  PMID: 12760861
23.  Gemifloxacin use in the treatment of acute bacterial exacerbation of chronic bronchitis 
The newest generation of fluoroquinolones have proven efficacy against bacterial organisms associated with acute exacerbation of chronic bronchitis (AECB). Gemifloxacin, as one of the quinolones in this class, exhibits many of the pharmacokinetic and pharmacodynamic characteristics of the class with a few notable differences. Against Streptococccus pneumoniae it has a lower minimal inhibitory concentration (MIC) than the other respiratory fluoroquinolones and it has activity against both bacterial DNA gyrase and topoisomerase IV. The increased activity of gemifloxacin against both enzymes may be associated with decreased rates of resistance. Clinically, gemifloxacin has been shown to have positive effects on length of hospitalization and increased success at long-term follow-up in AECB patients. These associations were observed in noninferiority comparison studies. Although an advantage with the use of gemifloxacin in AECB is suggested, there are no comparison data is available to conclude that gemifloxacin is superior to the other respiratory fluoroquinolones. Gemifloxacin is generally well tolerated, but is associated with a characteristic rash and gastrointestinal upset as its most common observed side effects.
PMCID: PMC2722869  PMID: 19684863
gemifloxacin; respiratory fluoroquinolones; acute exacerbation of chronic bronchitis
24.  Pharmacokinetics of the New Ketolide Telithromycin (HMR 3647) Administered in Ascending Single and Multiple Doses 
Telithromycin (HMR 3647) is a novel ketolide antimicrobial with good activity against both common and atypical respiratory pathogens, including many resistant strains. This randomized, three-period crossover study determined the dose proportionality of telithromycin pharmacokinetics after single and multiple dosing in healthy subjects. In each treatment period, subjects received a single oral dose of 400, 800 or 1,600 mg of telithromycin followed 4 days later by the same dose once daily for 7 days. Blood and urine samples were taken throughout the study for determination of pharmacokinetic parameters for telithromycin and RU 76363, its main metabolite. Telithromycin and RU 76363 achieved steady state within 2 to 3 days of once-daily dosing. A slight accumulation of telithromycin was observed after 7 days of therapy, with values of the area under the concentration-time curve from 0 to 24 h approximately 1.5 times higher than those achieved with the single dose. The pharmacokinetics of telithromycin and RU 76363 deviated moderately from dose proportionality. At a dose of 800 mg/day, telithromycin attained mean maximal and trough plasma concentrations of 2.27 and 0.070 mg/liter respectively. Elimination was biphasic; initial and terminal half-lives were 2.87 and 9.81 h for the 800-mg dose. Study medication was well tolerated, although adverse events tended to be more frequent at the 1,600-mg dose. This study showed that telithromycin was generally well tolerated and suggests that a once-daily 800-mg oral dose of telithromycin maintains an effective concentration in plasma for the treatment of respiratory tract infections involving the key respiratory pathogens.
PMCID: PMC90256  PMID: 11120961
25.  Controlled Trial of a 5-Day Course of Telithromycin versus Doxycycline for Treatment of Mild to Moderate Scrub Typhus▿  
New antibiotics are required to have the antibacterial activity against doxycycline-resistant Orientia tsutsugamushi. An in vitro sensitivity study showed that telithromycin was more effective than erythromycin for Rickettsia, Bartonella, and Coxiella burnetii. In this prospective, open-label, randomized trial, we enrolled patients with mild-to-moderate scrub typhus. We compared the efficacy and safety of a 5-day telithromycin therapy with those of a 5-day doxycycline therapy at Chosun University Hospital or one of its two community-based affiliated hospitals (Jangheung Hospital and Cheomdan Hospital), which are all located in southwestern Korea, between September and December 2005. A total of 92 patients were randomly assigned to either the telithromycin group (n = 47) or the doxycycline group (n = 45). After the treatment, fever control time was 20.45 ± 12.9 h in the telithromycin group and 22.60 ± 21.44 h in the doxycycline group (P > 0.05). After the treatment, the cure rate was 100% in the telithromycin group and 97.8% in the doxycycline group (P > 0.05). Furthermore, there were no significant differences in time elapsed until such symptoms as headache, myalgia, and rash disappeared. No serious adverse events or death were noted following the treatment in both groups. There were no significant differences in adverse events. In conclusion, the efficacy and safety of a 5-day once-a-day regimen of 800 mg telithromycin were equivalent to those of a 5-day twice-a-day regimen of 100 mg doxycycline in patients with mild-to-moderate scrub typhus. Telithromycin could be considered a promising new antibacterial agent for patients with scrub typhus.
PMCID: PMC1891405  PMID: 17404000

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