cem-101 and Bacterial-Infections

The development of resistance to antibiotics has been ignored for a long time. But nowadays, increasing resistance is an important topic. For a decade no new antibiotics had been developed and it is not possible to quickly close this gap of new resistance and no new drugs. This work presents six new antibiotics (ceftaroline, ceftobiprole, solithromycin, tedizolid, ceftolozane/tazobactam, ceftazidime/avibactam). In part, only expert opinions are given due to lack of study results.The two 5th generation cephalosporins ceftaroline and ceftobiprole have beside their equivalent efficacy to ceftriaxone (ceftaroline) and cefipim (ceftobiprole) high activity against MRSA. The fluoroketolide solithromycin should help against macrolide-resistant pathogens and has been shown to be noninferior to the fluorochinolones. The oxazolidinone tedizolid is effective against linezolid-resistant MRSA. The two cephalosporins ceftolozane/tazobactam and ceftazidime/avibactam are not only effective against gram-negative pathogens, but they have a very broad spectrum. Due to the efficacy against extended-spectrum β‑lactamases, they can relieve the selection pressure of the carbapenems. We benefit from all new antibiotics which can take the selection pressure from other often used antibiotics. The increasing number of resistant gram-negative pathogens worldwide is alarming. Thus, focusing on the development of new drugs is extremely important.

Topics: Anti-Bacterial Agents; Azabicyclo Compounds; Bacterial Infections; Ceftaroline; Ceftazidime; Cephalosporins; Clinical Trials as Topic; Drug Approval; Drug Combinations; Drug Resistance, Multiple, Bacterial; Ephedrine; Humans; Macrolides; Methicillin-Resistant Staphylococcus aureus; Organophosphates; Oxazoles; Penicillanic Acid; Phenobarbital; Staphylococcal Infections; Tazobactam; Theophylline; Triazoles

Lipoglycopeptide, ketolide, and quinolone antibiotics are currently in clinical development, with specific advantages over available molecules within their respective classes. The lipoglycopeptide oritavancin is bactericidal against MRSA, vancomycin-resistant enterococci, and multiresistant Streptococcus pneumoniae, and proved effective and safe for the treatment of acute bacterial skin and skin structure infection (ABSSSI) upon administration of a single 1200 mg dose (two completed phase III trials). The ketolide solithromycin (two phase III studies recruiting for community-acquired pneumonia) shows a profile of activity similar to that of telithromycin, but in vitro data suggest a lower risk of hepatotoxicity, visual disturbance, and aggravation of myasthenia gravis due to reduced affinity for nicotinic receptors. Among quinolones, finafloxacin and delafloxacin share the unique property of an improved activity in acidic environments (found in many infection sites). Finafloxacin (phase II completed; activity profile similar to that of ciprofloxacin) is evaluated for complicated urinary tract and Helicobacter pylori infections. The other quinolones (directed towards Gram-positive pathogens) show improved activity on MRSA and multiresistant S. pneumoniae compared to current molecules. They are in clinical evaluation for ABSSSI (avarofloxacin (phase II completed), nemonoxacin and delafloxacin (ongoing phase III)), respiratory tract infections (zabofloxacin and nemonoxacin (ongoing phase III)), or gonorrhea (delafloxacin).

Topics: Anti-Bacterial Agents; Bacterial Infections; Drug Resistance, Bacterial; Glycopeptides; Humans; Lipoglycopeptides; Macrolides; Quinolones; Triazoles

We assessed the pharmacokinetics and safety of solithromycin, a fluoroketolide antibiotic, in a phase 1, open-label, multicenter study of 13 adolescents with suspected or confirmed bacterial infections. On days 3 to 5, the mean (standard deviation) maximum plasma concentration and area under the concentration versus time curve from 0 to 24 h were 0.74 μg/ml (0.61 μg/ml) and 9.28 μg · h/ml (6.30 μg · h/ml), respectively. The exposure and safety in this small cohort of adolescents were comparable to those for adults. (This study has been registered at ClinicalTrials.gov under registration no. NCT01966055.).

Topics: Adolescent; Adult; Anti-Bacterial Agents; Area Under Curve; Bacterial Infections; Child; Dried Blood Spot Testing; Female; Humans; Macrolides; Male; Patient Safety; Triazoles

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.

Topics: Anti-Bacterial Agents; Asia; Azithromycin; Bacterial Infections; Community-Acquired Infections; Epidemiological Monitoring; Europe; Haemophilus influenzae; Humans; International Cooperation; Ketolides; Latin America; Macrolides; Microbial Sensitivity Tests; Moraxella catarrhalis; Staphylococcus aureus; Streptococcus; Streptococcus pneumoniae; Triazoles; United States

CEM-101 is a novel fluoroketolide with reported high potency against diverse groups of Gram-positive (Micrococcus spp., viridans group streptococci, Corynebacterium spp. Listeria monocytogenes, Clostridium spp., etc.) and Gram-negative bacteria (Neisseria gonorrhoeae, Campylobacter jejuni, Helicobacter pylori, Bacteroides fragilis, Shigella spp., etc.), including mycoplasma and ureaplasma, as well as bacteria commonly associated with community-acquired respiratory tract infections and skin and skin structure infections. In this study, CEM-101 and comparator antimicrobials were tested against a collection of very low prevalence aerobic and anaerobic bacteria collected via the SENTRY Antimicrobial Surveillance Program platform. CEM-101 was highly active against all Gram-positive organisms (MIC(50), 0.015 microg/mL) as compared with telithromycin (MIC(50), 0.06 microg/mL), clarithromycin (MIC(50), 0.12 microg/mL), and erythromycin (MIC(50), 0.25 microg/mL). Among Gram-negative pathogens, CEM-101 also displayed a high potency against most strains (MIC(50), 4 microg/mL) but was found to be equivalent or less active when compared with other antimicrobials tested with MIC(50) values ranging from < or =0.12 microg/mL for levofloxacin to 8 microg/mL for telithromycin. Among the strict anaerobic species, CEM-101 activity mirrored that of the aerobic species: high activity against the Gram-positive anaerobes (MIC(50) results ranging from < or =0.03 microg/mL to 0.12 microg/mL) and equivalent or less susceptible against Gram-negative anaerobes. Our in vitro antimicrobial susceptibility results for CEM-101 demonstrate better activity compared with other MLS(B) class agents among a diverse group of uncommonly isolated bacterial pathogens; these results provide an impetus for possible expanded indications during Phase 2 and 3 clinical trials.

Topics: Anti-Bacterial Agents; Bacteria, Aerobic; Bacteria, Anaerobic; Bacterial Infections; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Macrolides; Microbial Sensitivity Tests; Molecular Structure; Triazoles

CEM-101 is a novel fluorinated macrolide-ketolide with potent activity against bacterial pathogens that are susceptible or resistant to other macrolide-lincosamide-streptogramin B (MLS(B))-ketolide agents. CEM-101 is being developed for oral and parenteral use in moderate to moderately severe community-acquired bacterial pneumonia. The objective of this study was to assess the activity of CEM-101 and comparators against contemporary respiratory tract infection (RTI) isolates. A worldwide sample of organisms was used, including Streptococcus pneumoniae [n=168; 59.3% erythromycin-resistant and 18 multidrug-resistant (MDR) serogroup 19A strains], Moraxella catarrhalis (n=21; 11 beta-lactamase positive), Haemophilus influenzae (n=100; 48 beta-lactamase positive), Haemophilus parainfluenzae and Haemophilus haemolyticus (n=12), and Legionella pneumophila (n=30). Testing and interpretation were performed using reference Clinical and Laboratory Standards Institute methods. CEM-101 was very potent against S. pneumoniae [minimum inhibitory concentration for 90% of the organisms (MIC90)=0.25 mg/L; highest MIC at 0.5 mg/L] and was 2- and > or =32-fold more active than telithromycin and clindamycin, respectively. CEM-101 also demonstrated potent activity against S. pneumoniae MDR-19A strains (MIC90=0.5 mg/L). CEM-101 was the most potent antimicrobial agent tested against L. pneumophila, with all MIC values at < or = 0.015 mg/L (telithromycin MIC90=0.03 mg/L). CEM-101 was as potent as azithromycin against Haemophilus spp. RTI pathogens (MIC90=2 mg/L), with no variations for beta-lactamase production. CEM-101 MIC values against M. catarrhalis were all at < or =0.5mg/L. Interestingly, CEM-101 potency was ca. 6 log(2) dilutions greater than telithromycin MIC results among 44 beta-haemolytic streptococci having telithromycin MICs > or = 2 mg/L. CEM-101 exhibited the greatest potency and widest spectrum of activity against RTI pathogens among the tested MLS(B)-ketolide agents (azithromycin, clarithromycin, erythromycin, telithromycin, clindamycin and quinupristin/dalfopristin) and was comparable overall with levofloxacin.

Topics: Anti-Bacterial Agents; Bacteria; Bacterial Infections; Community-Acquired Infections; Drug Resistance, Multiple, Bacterial; Humans; Macrolides; Microbial Sensitivity Tests; Respiratory Tract Infections; Triazoles

Solithromycin (formerly CEM-101) is a novel fluoroketolide with potent activity against bacterial pathogens that are susceptible or resistant to other MLS(B)-ketolide agents. The objective of this study was to assess the activity of solithromycin and comparator antimicrobials against a large number and variety of contemporary clinical bacterial pathogens collected in the United States (USA) and Europe during 2009.. During 2009, a total of 10,670 non-duplicated clinical isolates were collected from 52 medical centers located in the USA (27 centers; 6228 isolates) and Europe (25 centers; 4442 isolates). Susceptibility testing and interpretation were performed using CLSI reference methods.. Among 1363 Streptococcus pneumoniae isolates, 99.9% of the strains displayed solithromycin MIC values at ≤0.5 mg/L, and 100% were inhibited at an MIC of 1 mg/L. Solithromycin demonstrated activity and potency against Haemophilus influenzae comparable to azithromycin (MIC(50), 1 mg/L and MIC(90), 2 mg/L) and was very potent against all 313 Moraxella catarrhalis isolated (MIC(50), 0.06 mg/L and MIC(90), 0.12 mg/L). Against 4729 Staphylococcus aureus isolates, solithromycin (MIC(50), 0.06 mg/L and MIC(90), >4 mg/L) activity was greater against methicillin-susceptible isolates (MIC(50), 0.06 mg/L and MIC(90), 0.06 mg/L) compared to methicillin-resistant isolates (MIC(50), 0.06 mg/L and MIC(90), >4 mg/L). Solithromycin was very active against all 757 β-haemolytic streptococci (MIC(50), ≤0.03 mg/L and MIC(90), 0.06 mg/L) and 310 viridans group streptococci (MIC(50), ≤0.03 mg/L and MIC(90), 0.06 mg/L) evaluated.. This contemporary surveillance study utilizing clinical isolates shows that solithromycin exhibits favorable in vitro potency and spectrum of activity against bacterial pathogens most frequently isolated in community-acquired respiratory tract (CA-RTI) and skin and skin structure infections (SSSI).

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Bacteria; Bacterial Infections; Child; Child, Preschool; Europe; Humans; Infant; Infant, Newborn; Macrolides; Microbial Sensitivity Tests; Middle Aged; Triazoles; United States; Young Adult