Acquired resistance to macrolides in Pseudomonas aeruginosa from cystic fibrosis patients.

Cystic fibrosis (CF) patients receive chronic treatment with macrolides for their antivirulence and anti-inflammatory properties. We, however, previously showed that Pseudomonas aeruginosa, considered as naturally resistant to macrolides, becomes susceptible when tested in a eukaryotic medium rather than a conventional broth.We therefore looked for specific macrolide resistance determinants in 333 CF isolates from four European CF centres in comparison with 48 isolates from patients suffering from hospital-acquired pneumonia (HAP).Minimum inhibitory concentrations (MICs) of macrolides and ketolides measured in eukaryotic medium (RPMI-1640) were higher towards CF than HAP isolates. Gene sequencing revealed mutations at three positions (2045, 2046 and 2598) in domain V of 23S rRNA of 43% of sequenced CF isolates, but none in HAP isolates. Enzymes degrading extracellular polymeric substances also reduced MICs, highlighting a role of the mucoid, biofilm-forming phenotype in resistance. An association between high MICs and chronic azithromycin administration was evidenced, which was statistically significant for patients infected by the Liverpool Epidemic Strain.Thus, ribosomal mutations are highly prevalent in CF isolates and may spread in epidemic clones, arguing for prudent use of oral macrolides in these patients. Measuring MICs in RPMI-1640 could be easily implemented in microbiology laboratories to phenotypically detect resistance.

Solithromycin: A novel ketolide antibiotic.

PURPOSE: The pharmacology, pharmacokinetics, pharmacodynamics, antimicrobial activity, clinical safety, and current regulatory status of solithromycin are reviewed. SUMMARY: Solithromycin is a novel ketolide antibiotic developed for the treatment of community-acquired bacterial pneumonia (CABP). Its pharmacologic, pharmacokinetic, and pharmacodynamic properties provide activity against a broad range of intracellular organisms, including retained activity against pathogens displaying various mechanisms of macrolide resistance. Phase III clinical trials of solithromycin demonstrated noninferiority of both oral and i.v.-to-oral regimens of 5-7 days' duration compared with moxifloxacin for patients with moderately severe CABP. Nearly one third of patients receiving i.v. solithromycin experienced infusion-site reactions. Although no liver-related adverse events were reported in patients receiving oral solithromycin, more patients receiving i.v.-to-oral solithromycin experienced asymptomatic, transient transaminitis, with alanine transaminase levels of >3 to >5 times the upper limit, compared with those treated with moxifloxacin. These results led the Food and Drug Administration to conclude that the solithromycin new drug application was not approvable as filed, adding that the risk of hepatotoxicity had not yet been adequately characterized. The agency further recommended a comparative study of patients with CABP to include approximately 9,000 patients exposed to solithromycin in order to exclude drug-induced liver injury events occurring at a rate of 1 in 3,000 with 95% probability. CONCLUSION: Solithromycin is a novel ketolide antibiotic with activity against a broad spectrum of intracellular organisms, including those displaying macrolide resistance. While demonstrating noninferiority to a current first-line agent in the treatment of CABP, concerns for drug-induced liver injury and infusion-site reactions have placed its regulatory future in doubt.

Fluoroquinolone, Macrolide, and Ketolide Resistance in Haemophilus parainfluenzae from South Africa.

Fluoroquinolones and ketolides are among the drugs of choice for the treatment of Haemophilus parainfluenzae infections. There has been a report of an emerging fluoroquinolone and telithromycin resistance in H. parainfluenzae isolates from the private sector of KwaZulu-Natal Province of South Africa that necessitates molecular investigation. The aim of this study is to characterize these resistance delineating mutations in genes commonly associated with reduced susceptibility. Ten H. parainfluenzae isolates retrieved from the sputum of 10 patients with H. parainfluenzae pneumonia were subjected to sensitivity testing by the disc diffusion and CLSI broth microdilution methods, polymerase chain reaction (PCR) and DNA sequencing of selected genes associated with resistance were carried out, while repetitive extragenic palindromic PCR (REP-PCR) was used to ascertain clonality. Fluoroquinolone resistance was attributed to the following amino acid substitutions: S84F, D88Y in GyrA, and S84Y/L, S138T, and M198 L change in ParC of the isolates. The plasmid-mediated quinolone resistance gene aac-(6')-Ib-cr was detected for the first time in four isolates of H. parainfluenzae and D420 N change was observed in ParE in one isolate. Macrolide and ketolide resistance were ascribed to the resistance genes mef (A), msr (D), and erm (B) detected in the isolates. REP-PCR analysis showed that the isolates were not clonal. All the observed resistance mechanisms are first reports in Africa. There is an emerging fluoroquinolone and macrolide resistance in H. parainfluenzae in South Africa that is attributable to known/novel resistance mechanisms, necessitating the monitoring of this pathogen as a potential opportunistic pathogen in a country with a high HIV and AIDS prevalence.

Efficacy of Solithromycin (CEM-101) for Experimental Otitis Media Caused by Nontypeable Haemophilus influenzae and Streptococcus pneumoniae.

Solithromycin (CEM-101) is a "fourth-generation" macrolide, as it has three binding site and is acid stable. The three binding sites confer activity against bacteria resistant to the older macrolides and ketolides, including multidrug-resistant Streptococcus pneumoniae and nontypeable Haemophilus influenzae (NTHi). The objective of this study was to evaluate solithromycin pharmacokinetics (PK), middle ear fluid (MEF) concentrations, and microbiologic efficacy in a chinchilla model of experimental otitis media (EOM) due to strains of S. pneumoniae or NTHi. Plasma PK (maximum concentration of drug in serum [Cmax] and area under the concentration-time curve from 0 to 24 h [AUC0-24]) and middle ear fluid (MEF) concentrations were determined. Isolates with specified antimicrobial susceptibility patterns were inoculated directly into the middle ear (ME). Plasma and MEF were collected for PK and MEF cultures performed to determine efficacy. Solithromycin administered at 150 mg/kg of body weight/day resulted in Cmax and AUC0-24 values of 2.2 µg/ml and 27.4 µg · h/ml in plasma and 1.7 µg/ml and 28.2 µg · h/ml in extracellular MEF on day 1. By day 3, Cmax and AUC0-24 values had increased to 4.5 µg/ml and 54 µg · h/ml in plasma and 4.8 µg/ml and 98.6 µg · h/ml in extracellular MEF. For NTHi EOM, three isolates with MIC/minimal bactericidal concentration (MBC) ratios of 0.5/1 µg/ml (isolate BCH1), 2/2 µg/ml (isolate BMC1247C), and 4/4 µg/ml (isolate BMC1213C) were selected. The MEF of >85% of animals infected with BCH1 and BMC1247C was sterilized. For NTHi BMC1213, >85% of MEF cultures remained positive. For S. pneumoniae EOM, 3 isolates with MIC/MBC ratios of 0.06/0.125 µg/ml (S. pneumoniae 331), 0.125/1 µg/ml (S. pneumoniae CP-645 [MLSB phenotype]), and 0.5/2 µg/ml (CP-712 [mefA subclass mefA resistance]) were selected. Solithromycin sterilized MEF in 100% of animals infected with S. pneumoniae 331 and S. pneumoniae CP-645. ME infection persisted in 60% of animals infected with CP-712. In a model of EOM, solithromycin sterilized MEF in >85% of animals challenged with NTHi with an MIC of ≤2 µg/ml and 100% of ME infected with S. pneumoniae with an MIC of ≤0.125 µg/ml.

Cethromycin: a new ketolide antibiotic.

OBJECTIVE: To review the pharmacology, chemistry, microbiology, in vitro susceptibility, mechanism of resistance, pharmacokinetics, pharmacodynamics, clinical efficacy, safety, drug interactions, dosage, and administration of cethromycin, a new ketolide antibiotic. DATA SOURCES: Literature was obtained through searching PubMed (1950-October 2012), International Pharmaceutical Abstracts (1970-October 2012), and a bibliographic review of published articles. Search terms included cethromycin, ABT-773, ketolide antibiotic, and community-acquired pneumonia. STUDY SELECTION AND DATA EXTRACTION: All available in vitro and preclinical studies, as well as Phase 1, 2, and 3 clinical studies published in English were evaluated to summarize the pharmacology, chemistry, microbiology, efficacy, and safety of cethromycin in the treatment of respiratory tract infections. DATA SYNTHESIS: Cethromycin, a new ketolide, has a similar mechanism of action to telithromycin with an apparently better safety profile. Cethromycin displays in vitro activity against selected gram-positive, gram-negative, and atypical bacteria. The proposed indication of cethromycin is treatment of mild to moderate community-acquired bacterial pneumonia in patients aged 18 years or older. Based on clinical studies, the recommended dose is 300 mg orally once a day without regard to meals. Cethromycin has an orphan drug designation for tularemia, plague, and anthrax prophylaxis. The Food and Drug Administration denied approval for the treatment of community-acquired pneumonia in 2009; a recent noninferiority trial showed comparable efficacy between cethromycin and clarithromycin. Preliminary data on adverse effects suggest that cethromycin is safe and gastrointestinal adverse effects appear to be dose-related. CONCLUSIONS: Cethromycin appears to be a promising ketolide for the treatment of mild to moderate community-acquired pneumonia. It was denied approval by the FDA in 2009 pending more evidence to show its efficacy, with more recent studies showing its noninferiority to antibiotics for the same indication.

Cethromycin: a promising new ketolide antibiotic for respiratory infections.

Community-acquired pneumonia remains the primary infectious cause of death in the United States. At current levels of antimicrobial resistance, conventional agents are at risk of becoming less effective, and the need for new agents is pressing. Cethromycin is a new ketolide antibiotic being investigated for use in respiratory tract infections. To review its pharmacology, in vitro susceptibilities, pharmacokinetics, efficacy, safety, and drug interactions, we conducted a MEDLINE search restricted to English-language articles citing cethromycin or ABT-773 (its original designation) from 1990-May 2009. Additional data sources were identified from the references of selected articles. All published trials and available poster data citing cethromycin were selected for review. In vitro, cethromycin displays more potent antibacterial effects than its predecessor telithromycin. Cethromycin exhibits potent inhibition of both gram-positive and gram-negative respiratory pathogens. A new drug application for cethromycin was submitted to the United States Food and Drug Administration in 2008 for the treatment of community-acquired pneumonia. Clinical trial data in the treatment of respiratory tract infections support cethromycin's efficacy. The limited safety data have not included any reports of hepatotoxicity. If cethromycin proves to be safe with regard to hepatotoxicity, it has great promise as an alternative to current standard therapy for community-acquired respiratory infections, especially pneumonia. Given current resistance levels, cethromycin could provide more reliable coverage against common respiratory pathogens than traditional agents in the beta-lactam and macrolide classes.

Discovery of azetidinyl ketolides for the treatment of susceptible and multidrug resistant community-acquired respiratory tract infections.

Respiratory tract bacterial strains are becoming increasingly resistant to currently marketed macrolide antibiotics. The current alternative telithromycin (1) from the newer ketolide class of macrolides addresses resistance but is hampered by serious safety concerns, hepatotoxicity in particular. We have discovered a novel series of azetidinyl ketolides that focus on mitigation of hepatotoxicity by minimizing hepatic turnover and time-dependent inactivation of CYP3A isoforms in the liver without compromising the potency and efficacy of 1.

Use of cethromycin, a new ketolide, for treatment of community-acquired respiratory infections.

BACKGROUND: The ketolides are a subclass of macrolides, which were designed specifically to overcome macrolide-resistant respiratory pathogens. Ketolides lack the cladinose sugar, which is replaced with a 3-ketone group. Ketolides bind to a secondary region on domain II of the 23S rRNA subunit. Telithromycin was the first ketolide to be approved by the FDA in 2004 for treatment of community-acquired pneumonia (CAP), acute exacerbations of chronic bronchitis (AECB) and sinusitis. However, in 2006, after reports of serious hepatotoxicity, the FDA issued a public health advisory followed by a warning. In 2007 the indications for treatment of AECB and sinusitis were removed from the labeling. Cethromycin (ABT-773) is the only other ketolide currently under clinical development. OBJECTIVE: To review currently available data on cethromycin, including chemistry, in vitro activity, pharmacokinetics, pharmacodynamics, in vivo activity and results of treatment studies in humans. METHODS: A search was made in PubMed, pharmaceutical databases and meeting abstracts using the terms ketolides, ABT-773 and cethromycin. RESULTS/CONCLUSIONS: Cethromycin has comparable tissue penetration, pharmacokinetics and in vitro activity compared with telithromycin to Streptococcus pneumoniae, including multidrug-resistant isolates, Haemophilus influenzae, Moraxella catarrhalis, Chlamydophila pneumoniae, Mycoplasma pneumoniae and Legionella pneumophila. There is only one published CAP treatment study that compared cethromycin 150 mg q.d. with 150 mg b.i.d. One Phase II and a Phase II/III study have been presented in abstract form, both were non-comparative, dose-ranging studies, which suggested that 150 mg q.d. or 300 mg q.d. were comparable in terms of clinical response and bacterial eradication, although data on the latter are limited. Data on side effects are limited and appear to be mainly gastrointestinal. There have been no reports of serious hepatotoxicity at the time of this writing. Cethromycin may have other uses in addition to treatment of CAP respiratory infections, including treatment of infections due to Neisseria gonorrhoeae and Chlamydia trachomatis and bioterrorism agents including Bacillus anthracis, Yersinia pestis and Francisella tularensis.

Clinical implications of macrolide resistance in community-acquired respiratory tract infections.

Laboratory surveillance data suggest that macrolide resistance among Streptococcus pneumoniae has increased dramatically over the past 15 years. This review examines the specifics of macrolide resistance and the clinical relevance of in vitro susceptibility testing in light of the pharmacokinetics and pharmacodynamics of azithromycin and clarithromycin. These drugs concentrate extensively within respiratory tissue and have other positive characteristics not reflected by in vitro susceptibility testing. In general, clarithromycin is the most potent macrolide and the one most likely to maintain clinical efficacy against the low-level resistance associated with most macrolide-resistant pneumococci in the USA. These findings suggest that susceptibility data may underestimate clinical utility and that clarithromycin still has a place in the empiric treatment of respiratory infections.

Treatment of experimental chronic pulmonary mycoplasmosis.

Mycoplasma pneumoniae infection has been associated with chronic lung disease. Treatment of chronic pulmonary mycoplasmosis has not been well investigated. BALB/c mice were intranasally inoculated once with M. pneumoniae or with sterile media (uninfected controls). Infected mice were treated with telithromycin or placebo daily for 10 days in the chronic phase of disease (18 months after inoculation). Mice (n=43) were evaluated before therapy and 1 day after completion of telithromycin. Treatment of infected mice with telithromycin at 18 months after infection significantly reduced chronic pulmonary histological inflammation compared with infected mice given placebo; however, this treatment did not improve airway obstruction or airway hyperresponsiveness. Therapy longer than 10 days may be necessary to improve pulmonary function.

[Antibiotics for acute exacerbations of chronic obstructive pulmonary disease (COPD)]. / Indications et choix de l'antibiothérapie d'une exacerbation de bronchopneumopathie chronique obstructive (BPCO).

OBJECTIVE: This study had for aim to evaluate the rationale and indications for antibiotic treatment in acute exacerbations of COPD and to identify potential differences among various antibiotics available for the treatment of exacerbations in France. METHODS: A search was performed in Medline and for references quoted in identified articles from 1995 to 2005. Open or blind randomized studies involving antibiotics available in France were reviewed. RESULTS: About 50% of all exacerbations are related to bacterial infection. Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae are the main pathogens responsible for bacterial exacerbations. Pseudomonas aeruginosa and enterobacter spp are frequently found in patients with severe functional impairment. Increased purulence of sputum is associated with bacterial infection. Patients with severe functional impairment benefit the most from antibiotic treatment. Although new molecules have larger antibiotic spectrum and better pharmacological properties, the evidence supporting their use compared to standard therapy remains scarce. CONCLUSIONS: Additional studies are needed to better identify the subset of patients benefiting from antibiotics and to determine whether new molecules produce significant improvement on relevant outcomes such as exacerbation free interval compared to standard therapy.

Telithromycin in the treatment of pneumococcal community-acquired respiratory tract infections: a review.

OBJECTIVES: A pooled analysis of 14 Phase III studies was performed to establish the clinical and bacteriologic efficacy of telithromycin 800 mg once daily in the treatment of pneumococcal community-acquired respiratory tract infections (RTIs). METHODS: Data were examined from 5534 adult/adolescent patients with community-acquired pneumonia (CAP), acute exacerbations of chronic bronchitis (AECB), or acute bacterial sinusitis, who had received telithromycin for 5-10 days or a comparator antibacterial. RESULTS: Streptococcus pneumoniae was identified in 704/2060 (34.2%) bacteriologically evaluable patients. The respective per-protocol clinical cure rates for telithromycin and comparators were 94.3% and 90.0% (CAP); 81.5% and 78.9% (AECB); 90.1% and 87.5% (acute sinusitis); 92.7% and 87.6% (all indications). Clinical cure rates were 28/34 (82.4%) and 5/7, respectively, for penicillin-resistant infections, and 44/52 (84.6%) and 11/14, respectively, for erythromycin-resistant infections. Of 82 patients with pneumococcal bacteremia, 74 (90.2%) were clinically cured after telithromycin treatment, including 5/7 and 8/10 with penicillin- or erythromycin-resistant strains, respectively. Adverse events considered possibly related to study medication were reported by 1071/4045 (26.5%) telithromycin and 505/1715 (29.4%) comparator recipients. These events were generally of mild/moderate severity, and mainly gastrointestinal in nature. CONCLUSIONS: As S. pneumoniae is the leading bacterial cause of community-acquired RTIs, and antibacterial resistance is increasing among this species, these findings support the use of telithromycin as first-line therapy in this setting.

Efficacy of oral telithromycin in community-acquired pneumonia caused by resistant Streptococcus pneumoniae.

The efficacy of oral telithromycin 800mg once daily for 7 days was evaluated in a multicentre, multinational study in patients with community-acquired pneumonia caused by Streptococcus pneumoniae resistant to penicillin and/or erythromycin. Per-protocol clinical and bacteriological outcomes were assessed 10-17 days post-therapy. Of the 129 patients with S. pneumoniae infection, 16 were infected with strains resistant to penicillin and/or erythromycin. Fifteen of these 16 patients (93.8%) were assessed as clinically and bacteriologically cured at the post-therapy visit.

Telithromycin: the first ketolide for the treatment of respiratory infections.

PURPOSE: The pharmacology, mechanisms of resistance, in vitro activity, clinical efficacy, pharmacokinetics, indications, adverse effects, dosage and administration, and place in therapy of telithromycin in the treatment of respiratory infections are reviewed. SUMMARY: Telithromycin is the first ketolide to be approved in the United States for use against common respiratory pathogens. The unique structure of telithromycin allows for enhanced binding to bacterial ribosomal RNA, thereby blocking protein synthesis. Its spectrum of activity includes pathogens implicated in common respiratory infections (Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumonia, and Chlamydia pneumoniae) and multidrug-resistant isolates of pneumococcus. Clinical efficacy has been documented in several multicenter, comparative trials for the treatment of community-acquired pneumonia, acute exacerbation of chronic bronchitis, acute maxillary sinusitis, and pharyngitis tonsillitis. Although studies have demonstrated that the clinical efficacy of telithromycin is comparable to macrolides, telithromycin is unique in that it provides activity against penicillin- and macrolide-resistant respiratory pathogens. The recommended dosage of telithromycin is 800 mg p.o. once daily. The most common adverse events resulting from telithromycin use include diarrhea, nausea, headache, dizziness, vomiting, loose stools, dysgeusia, and dyspepsia. The drug's adverse-event profile is comparable to that of similar agents. Telithromycin is a strong inhibitor of cytochrome P-450 isoenzyme 3A4; therefore, it can affect the efficacy and toxicity profile of medications that are metabolized by this isoenzyme. CONCLUSION: Telithromycin is a reasonable addition to the current treatment options for upper-respiratory-tract infections. Its use should be restricted to infections caused by penicillin- and macrolide-resistant pathogens.

Antibiotic activity of telithromycin and comparators against bacterial pathogens isolated from 3,043 patients with acute exacerbation of chronic bronchitis.

BACKGROUND: Antimicrobial therapy is considered an important component in the medical management of most patients with acute exacerbation of chronic bronchitis (AECB). The three predominant bacterial species isolated are nontypeable Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae. Staphylococcus aureus is also frequently isolated while atypical bacteria are thought to cause up to 10% of exacerbations. Antibacterial resistance is increasing worldwide and little surveillance data exist concerning pathogens isolated from patients with AECB. METHODS: This study examines the prevalence of antibacterial resistance in isolates obtained from patients with clinically diagnosed AECB. A total of 3043 isolates were obtained from 85 centres in 29 countries, between 1999-2003, and were tested against the new ketolide telithromycin and a panel of commonly used antibiotics. RESULTS AND DISCUSSION: Of the S. pneumoniae isolates, 99.9% were susceptible to telithromycin, but only 71% were susceptible to erythromycin and 75.3% to penicillin. Of the H. influenzae isolates, 99.6% were susceptible to telithromycin. 11.7% of these isolates produced beta-lactamase. Almost 10% of S. pneumoniae were multidrug-resistant; 99.0% of these isolates were susceptible to telithromycin. Telithromycin also demonstrated good in vitro activity against M. catarrhalis (MIC90 = 0.12 mg/L) and was the most active compound against methicillin-susceptible S. aureus (98.9% susceptible). CONCLUSION: Telithromycin demonstrated similar or better activity against the bacterial species investigated than the other agents, with the most complete coverage overall. These species are the predominant causative bacterial pathogens in AECB and thus the spectrum of activity of telithromycin makes it a potential alternative for the empirical treatment of AECB.

Glucocorticoids increase in vitro and in vivo activities of antibiotics against Chlamydophila pneumoniae.

The in vitro and in vivo antichlamydial activities of dexamethasone and beclomethasone alone and in combination with an antibiotic were tested. In vitro, dexamethasone and beclomethasone decreased the number of inclusion-forming units versus the control number (P < 0.001). The combination of glucocorticoids with azithromycin, telithromycin, or levofloxacin was more active than antibiotics used alone (P < 0.001). The combination, tested in a murine Chlamydophila pneumoniae infection model, produced similar results.

Development of macrolide-resistance and comparative activity of telithromycin in streptococci in Austria, 1996-2002.

The increase detected in macrolide resistance in streptococci in various parts of the world has brought into question the usefulness of macrolides as first line therapy for respiratory tract infections. In a nationwide study, a total of 3012 Streptococcus pneumoniae and 499 Streptococcus pyogenes isolates were collected from 1996 to 2002 and tested for their susceptibility to penicillin, azithromycin, clarithromycin and telithromycin (2002 only). Penicillin-intermediate and -resistant isolates of S. pneumoniae comprised 4.9% (2.9 and 2.0%, respectively) of all isolates in 1996; macrolide resistance was also comparatively low at 3.2%. In the following years the rate of penicillin-resistant pneumococci increased steadily, reaching the 10% mark in 2002. A similar trend was recorded for the macrolides. No penicillin-resistant strain of S. pyogenes was found during the observation period. The prevalence of macrolide-resistance in S. pyogenes climbed from 4.7% in 1996 to the present rate of 7.2% (clarithromycin) and 9.4% (azithromycin). Telithromycin showed excellent activity against both S. pneumoniae and S. pyogenes with 99.8 and 100% strains sensitive, respectively.

Efficacy of telithromycin in the treatment of experimental Bacteroides fragilis intraabdominal abscess in the senescent mice.

The efficacy of telithromycin (HMR 3647), a new ketolide, in the treatment of experimental Bacteroides fragilis intraabdominal abscess in young and senescent mice was evaluated. Two different age groups of mice, young (2-3 months) and senescent (18-24 months) were used in this study. Telithromycin (50mg/kg/bid) was compared with clindamycin and metronidazole, both administered in 100 mg/kg/bid doses. Telithromycin cured the infection in 74% of the young and 67% of the old mice but this difference was not significant. Telithromycin efficacy was comparable to that of clindamycin which cured 82% of the young and 75% of the old, but was superior to the efficacy of metronidazole, which cured 61% of the young and 50% of the senescent mice. Young animals that were not cured by any of the three antibiotics showed decrease in the viable bacterial cell counts by two logs while the senescent mice had a one log difference. Serum, pus and tissue concentrations of telithromycin were five-fold higher in the old mice than in the young. Age by itself had no adverse effect on therapeutic outcome of any of the three antibiotics used.