RESUMO
Antimicrobial resistance (AMR) is a major global health threat estimated to have caused the deaths of 1.27 million people in 2019, which is more than HIV/AIDS and malaria deaths combined. AMR also has significant consequences on the global economy. If not properly addressed, AMR could immensely impact the world's economy, further increasing the poverty burden in low- and middle-income countries. To mitigate the risk of a post-antibiotic society, where the ability to effectively treat common bacterial infections is being severely threatened, it is necessary to establish a continuous supply of new and novel antibacterial medicines. However, there are gaps in the current pipeline that will prove difficult to address, given the time required to develop new agents. To understand the status of upstream antibiotic development and the challenges faced by drug developers in the early development stage, the World Health Organization has regularly assessed the preclinical and clinical antibacterial development pipeline. The review identifies potential new classes of antibiotics or novel mechanisms of action that can better address resistant bacterial strains. This proactive approach is necessary to stay ahead of evolving resistance patterns and to support the availability of effective treatment options. This review examines the trends in preclinical development and attempts to identify gaps and potential opportunities to overcome the numerous hurdles in the early stages of the antibacterial research and development space.
Assuntos
Antibacterianos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Humanos , Desenvolvimento de Medicamentos , Saúde Global , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/microbiologia , Farmacorresistência Bacteriana , Animais , Avaliação Pré-Clínica de Medicamentos , Organização Mundial da SaúdeRESUMO
There is an urgent global need for new strategies and drugs to control and treat multidrug-resistant bacterial infections. In 2017, the World Health Organization (WHO) released a list of 12 antibiotic-resistant priority pathogens and began to critically analyze the antibacterial clinical pipeline. This review analyzes "traditional" and "nontraditional" antibacterial agents and modulators in clinical development current on 30 June 2021 with activity against the WHO priority pathogens mycobacteria and Clostridioides difficile. Since 2017, 12 new antibacterial drugs have been approved globally, but only vaborbactam belongs to a new antibacterial class. Also innovative is the cephalosporin derivative cefiderocol, which incorporates an iron-chelating siderophore that facilitates Gram-negative bacteria cell entry. Overall, there were 76 antibacterial agents in clinical development (45 traditional and 31 nontraditional), with 28 in phase 1, 32 in phase 2, 12 in phase 3, and 4 under regulatory evaluation. Forty-one out of 76 (54%) targeted WHO priority pathogens, 16 (21%) were against mycobacteria, 15 (20%) were against C. difficile, and 4 (5%) were nontraditional agents with broad-spectrum effects. Nineteen of the 76 antibacterial agents have new pharmacophores, and 4 of these have new modes of actions not previously exploited by marketed antibacterial drugs. Despite there being 76 antibacterial clinical candidates, this analysis indicated that there were still relatively few clinically differentiated antibacterial agents in late-stage clinical development, especially against critical-priority pathogens. We believe that future antibacterial research and development (R&D) should focus on the development of innovative and clinically differentiated candidates that have clear and feasible progression pathways to the market.
Assuntos
Infecções Bacterianas , Clostridioides difficile , Infecções por Bactérias Gram-Negativas , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Farmacorresistência Bacteriana Múltipla , Bactérias Gram-Negativas , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/microbiologia , HumanosRESUMO
Solithromycin (CEM-101) is a novel fluoroketolide antimicrobial agent with activity against typical and atypical pathogens associated with community-acquired bacterial pneumonia. Using a neutropenic murine lung infection model, the objectives of this study were to identify the pharmacokinetic/pharmacodynamic (PK/PD) index most closely associated with efficacy and the magnitude of such indices associated with solithromycin efficacy against Streptococcus pneumoniae Plasma and epithelial lining fluid (ELF) samples for pharmacokinetics (PK) were collected serially over 24 hours from healthy mice administered single doses of solithromycin (0.625 to 40 mg/kg). Neutropenic CD-1 mice infected with 108 CFUs of one of five S. pneumoniae isolates were administered solithromycin (0.156 to 160 mg/kg/day) via oral gavage. Doses were administered in a fractionated manner for mice infected with one isolate, while mice infected with the remaining four isolates received solithromycin as either a regimen every 6 hours or every 12 hours. A three-compartment model best described solithromycin PK in the plasma and ELF (r2 = 0.935 and 0.831, respectively). The ratio of total-drug ELF to free-drug plasma area under the concentration-time curve (AUC) from time 0 to 24 hours was 2.7. Free-drug plasma and total-drug ELF AUC to minimum inhibitory concentration ratios (AUC/MIC ratios) were most predictive of efficacy (r2 = 0.851 and 0.850, respectively). The magnitude of free-drug plasma/total-drug ELF AUC/MIC ratios associated with net bacterial stasis and a 1- and 2-log10 CFU reduction from baseline was 1.65/1.26, 6.31/15.1, and 12.8/59.8, respectively. These data provided dose selection support for solithromycin for clinical trials in patients with community-acquired bacterial pneumonia.
Assuntos
Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Pulmão/microbiologia , Macrolídeos/farmacocinética , Macrolídeos/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/patogenicidade , Triazóis/farmacocinética , Triazóis/uso terapêutico , Animais , Feminino , Camundongos , Testes de Sensibilidade Microbiana , Streptococcus pneumoniae/genéticaRESUMO
PURPOSE: Macrolide antibiotics are commonly prescribed treatments for drug-resistant bacterial infections; however, many macrolides have been shown to cause liver enzyme elevations and one macrolide, telithromycin, has been pulled from the market by its provider due to liver toxicity. This work seeks to assess the mechanisms responsible for the toxicity of macrolide antibiotics. METHODS: Five macrolides were assessed in in vitro systems designed to test for bile acid transporter inhibition, mitochondrial dysfunction, and oxidative stress. The macrolides were then represented in DILIsym, a quantitative systems pharmacology (QST) model of drug-induced liver injury, placing the in vitro results in context with each compound's predicted liver exposure and known biochemistry. RESULTS: DILIsym results suggest that solithromycin and clarithromycin toxicity is primarily due to inhibition of the mitochondrial electron transport chain (ETC) while erythromycin toxicity is primarily due to bile acid transporter inhibition. Telithromycin and azithromycin toxicity was not predicted by DILIsym and may be caused by mechanisms not currently incorporated into DILIsym or by unknown metabolite effects. CONCLUSIONS: The mechanisms responsible for toxicity can be significantly different within a class of drugs, despite the structural similarity among the drugs. QST modeling can provide valuable insight into the nature of these mechanistic differences.
Assuntos
Antibacterianos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Fígado/efeitos dos fármacos , Macrolídeos/efeitos adversos , Modelos Biológicos , Animais , Células CHO , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/metabolismo , Cricetulus , Células Hep G2 , Humanos , Fígado/metabolismo , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacosRESUMO
Staphylococcal biofilms are a major cause of therapeutic failure, especially when caused by multiresistant strains. Oral fusidic acid is currently being redeveloped in the United States for skin, skin structure, and orthopedic infections, in which biofilms play a major role. The aim of this study was to examine the activity of fusidic acid alone or combined with other antistaphylococcal drugs against biofilms made by a reference strain and five clinical isolates of Staphylococcus aureus or Staphylococcus epidermidis in in vitro static and dynamic models (microtiter plates and a CDC reactor) exposed to clinically relevant concentrations. In microtiter plates, antibiotics alone were poorly active, with marked differences among strains. At concentrations mimicking the free-drug human maximum concentration of drug in serum (Cmax), the combination of fusidic acid with linezolid, daptomycin, or vancomycin resulted in increased activity against 4 to 5 strains, while the combination with doxycycline, rifampin, or moxifloxacin increased activity against 1 to 3 strains only. In the CDC reactor, biofilms were grown under constant flow and antibiotic concentrations decreased over time according to human elimination rates. A bactericidal effect was obtained when fusidic acid was combined with daptomycin or linezolid, but not with vancomycin. The higher tolerance of biofilms to antibiotics in the CDC reactor is probably attributable to the more complex architecture they adopt when growing under constant flow. Because biofilms grown in the CDC reactor are considered more similar to those developing in vivo, the data support further testing of combinations of fusidic acid with daptomycin or linezolid in models pertinent to chronic skin, skin structure, or orthopedic infections.
Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Daptomicina/farmacologia , Ácido Fusídico/farmacologia , Humanos , Testes de Sensibilidade Microbiana , Moxifloxacina/farmacologia , Rifampina/farmacologia , Staphylococcus epidermidis/efeitos dos fármacosRESUMO
Solithromycin, a novel macrolide and the first fluoroketolide, is being developed as a therapy for community-acquired bacterial pneumonia, with a distinct mechanism that provides activity against macrolide-resistant bacteria. The pharmacokinetics, metabolism, and excretion of solithromycin were studied in healthy male subjects after oral administration of a single 800-mg (â¼100-µCi) dose of [14C]solithromycin. Solithromycin was well tolerated, and absorption from the solution occurred with a median time to peak concentration of 4.0 h. Solithromycin and the total radioactivity had similar profiles with no long-lived metabolites. The whole-blood total radioactivity was approximately 75% of the plasma total radioactivity. Recovery was essentially complete (mean, 90.6%), with 76.5% and 14.1% of the dose recovered in feces and urine, respectively. Unchanged solithromycin (CEM-101) was the predominant circulating radioactive component in plasma (77% of the total radioactivity area under the concentration-time curve [AUC]), with two minor plasma metabolites, CEM-214 and CEM-122 (N-acetyl-CEM-101), each accounting for approximately 5% of the total radioactivity. Urinary excretion was predominantly like that of the parent. Solithromycin was primarily eliminated in the feces after extensive metabolism via a complex metabolic pathway with CEM-262 as the major constituent (27.36% of the administered dose). Overall oxidative pathways, presumably carried out mostly by CYP3A4, represented the majority of the metabolism, with N-acetylation present to a lesser extent. No disproportionate human metabolites were observed.
Assuntos
Antibacterianos/metabolismo , Antibacterianos/farmacocinética , Infecções Comunitárias Adquiridas/tratamento farmacológico , Macrolídeos/metabolismo , Macrolídeos/farmacocinética , Pneumonia Bacteriana/tratamento farmacológico , Triazóis/metabolismo , Triazóis/farmacocinética , Adulto , Citocromo P-450 CYP3A/metabolismo , Humanos , Masculino , Taxa de Depuração Metabólica/fisiologia , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Macrolide antibiotics may cause QT prolongation. OBJECTIVES: To study the QT effect of a novel macrolide, solithromycin. METHODS: This was a thorough QT study with a three-way crossover design performed in healthy male and female subjects to evaluate the ECG effects of a novel macrolide, solithromycin. Forty-eight subjects were randomized to receive 800 mg of intravenous (iv) solithromycin, 400 mg of oral moxifloxacin and placebo in three separate treatment periods. Continuous 12 lead ECGs were recorded at a pre-dose baseline and serially after drug administration for 24 h. RESULTS: After the 40 min infusion of 800 mg of solithromycin, the geometric mean solithromycin peak plasma concentration (Cmax) reached 5.9 (SD: 1.30) µg/mL. Solithromycin infusion caused a heart rate increase with a peak effect of 15 bpm immediately after the end of the infusion. The change-from-baseline QTcF (ΔQTcF) was similar after dosing with solithromycin and placebo and the resulting placebo-corrected ΔQTcF (ΔΔQTcF) for solithromycin was therefore small at all timepoints with a peak effect at 4 h of only 2.8 ms (upper bound of the 90% CI: 4.9 ms). Using a linear exposure-response model, a statistically significant, slightly negative slope of -0.86 ms per ng/mL (90% CI: -1.19 to -0.53; Pâ=â0.0001) was observed with solithromycin. The study's ability to detect small QT changes was confirmed by the moxifloxacin response. Solithromycin did not have a clinically meaningful effect on the PR or QRS interval. CONCLUSIONS: The study demonstrated that solithromycin, unlike other macrolide antibiotics, does not cause QT prolongation.
Assuntos
Arritmias Cardíacas/induzido quimicamente , Sistema de Condução Cardíaco/efeitos dos fármacos , Macrolídeos/efeitos adversos , Triazóis/efeitos adversos , Estudos Cross-Over , Eletrocardiografia , Feminino , Fluoroquinolonas/uso terapêutico , Voluntários Saudáveis , Humanos , Macrolídeos/sangue , Macrolídeos/uso terapêutico , Masculino , Moxifloxacina , Placebos/administração & dosagem , Triazóis/sangue , Triazóis/uso terapêuticoRESUMO
BACKGROUND: Solithromycin, a novel macrolide antibiotic with both intravenous and oral formulations dosed once daily, has completed 2 global phase 3 trials for treatment of community-acquired bacterial pneumonia. METHODS: A total of 863 adults with community-acquired bacterial pneumonia (Pneumonia Outcomes Research Team [PORT] class II-IV) were randomized 1:1 to receive either intravenous-to-oral solithromycin or moxifloxacin for 7 once-daily doses. All patients received 400 mg intravenously on day 1 and were permitted to switch to oral dosing when clinically indicated. The primary objective was to demonstrate noninferiority (10% margin) of solithromycin to moxifloxacin in achievement of early clinical response (ECR) assessed 3 days after first dose in the intent-to-treat (ITT) population. Secondary endpoints included demonstrating noninferiority in ECR in the microbiological ITT population (micro-ITT) and determination of investigator-assessed success rates at the short-term follow-up (SFU) visit 5-10 days posttherapy. RESULTS: In the ITT population, 79.3% of solithromycin patients and 79.7% of moxifloxacin patients achieved ECR (treatment difference, -0.46; 95% confidence interval [CI], -6.1 to 5.2). In the micro-ITT population, 80.3% of solithromycin patients and 79.1% of moxifloxacin patients achieved ECR (treatment difference, 1.26; 95% CI, -8.1 to 10.6). In the ITT population, 84.6% of solithromycin patients and 88.6% of moxifloxacin patients achieved clinical success at SFU based on investigator assessment. Mostly mild/moderate infusion events led to higher incidence of adverse events overall in the solithromycin group. Other adverse events were comparable between treatment groups. CONCLUSIONS: Intravenous-to-oral solithromycin was noninferior to intravenous-to-oral moxifloxacin. Solithromycin has potential to provide an intravenous and oral option for monotherapy for community-acquired bacterial pneumonia. CLINICAL TRIALS REGISTRATION: NCT01968733.
Assuntos
Antibacterianos/administração & dosagem , Infecções Comunitárias Adquiridas/tratamento farmacológico , Infecções Comunitárias Adquiridas/microbiologia , Fluoroquinolonas/administração & dosagem , Macrolídeos/administração & dosagem , Pneumonia Bacteriana/tratamento farmacológico , Pneumonia Bacteriana/microbiologia , Triazóis/administração & dosagem , Administração Intravenosa , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/efeitos adversos , Infecções Comunitárias Adquiridas/diagnóstico , Comorbidade , Farmacorresistência Bacteriana , Feminino , Fluoroquinolonas/efeitos adversos , Humanos , Macrolídeos/efeitos adversos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Moxifloxacina , Pneumonia Bacteriana/diagnóstico , Resultado do Tratamento , Triazóis/efeitos adversosRESUMO
There has been an increase in the number of pertussis cases reported since the introduction of the acellular pertussis vaccine. While children that present with pertussis have a characteristic whooping cough, adults can simply have a persistent, nonspecific cough and remain undiagnosed. Macrolide antibiotics, such as azithromycin, are the currently recommended treatment for pertussis. Solithromycin is a new macrolide and the first fluoroketolide with broad activity against a wide spectrum of bacterial pathogens and has completed clinical development for community-acquired bacterial pneumonia. This study reports the potent in vitro activity of solithromycin against a collection of recent isolates of Bordetella pertussis.
Assuntos
Antibacterianos/farmacologia , Bordetella pertussis/efeitos dos fármacos , Macrolídeos/farmacologia , Triazóis/farmacologia , Bordetella pertussis/isolamento & purificação , Humanos , Testes de Sensibilidade MicrobianaRESUMO
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.).
Assuntos
Antibacterianos/farmacocinética , Infecções Bacterianas/tratamento farmacológico , Macrolídeos/farmacocinética , Triazóis/farmacocinética , Adolescente , Adulto , Antibacterianos/sangue , Área Sob a Curva , Infecções Bacterianas/sangue , Criança , Teste em Amostras de Sangue Seco , Feminino , Humanos , Macrolídeos/sangue , Masculino , Segurança do Paciente , Triazóis/sangueRESUMO
The macrolide class of antibiotics, including the early generation macrolides erythromycin, clarithromycin and azithromycin, have been used broadly for treatment of respiratory tract infections. An increase of treatment failures of early generation macrolides is due to the upturn in bacterial macrolide resistance to 48% in the US and over 80% in Asian countries and has led to the use of alternate therapies, such as fluoroquinolones. The safety of the fluoroquinolones is now in question and alternate antibiotics for the outpatient treatment of community acquired bacterial pneumonia are needed. Telithromycin, approved in 2003, is no longer used owing to serious adverse events, collectively called the 'Ketek effects'. Telithromycin has a side chain pyridine moiety that blocks nicotinic acetylcholine receptors. Blockade of these receptors is known experimentally to cause the side effects seen with telithromycin in patients use. Solithromycin is a new macrolide, the first fluoroketolide, which has been tested successfully in two Phase 3 trials and is undergoing regulatory review at the FDA. Solithromycin is differentiated from telithromycin chemically and biologically in that its side chain is chemically different and does not significantly block nicotinic acetylcholine receptors. Solithromycin was well tolerated and effective in clinical trials.
Assuntos
Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Macrolídeos/farmacologia , Infecções Respiratórias/tratamento farmacológico , Triazóis/farmacologia , Antibacterianos/administração & dosagem , Antibacterianos/química , Relação Dose-Resposta a Droga , Humanos , Macrolídeos/administração & dosagem , Macrolídeos/química , Testes de Sensibilidade Microbiana , Conformação Molecular , Triazóis/administração & dosagem , Triazóis/químicaRESUMO
BACKGROUND: Progressive resistance to antimicrobial agents has reduced options for gonorrhea therapy worldwide. Solithromycin (CEM-101) is a novel oral fluoroketolide antimicrobial with substantial in vitro activity against Neisseria gonorrhoeae. METHODS: We conducted a phase 2 trial of 2 oral doses of solithromycin (1200 and 1000 mg) for treatment of uncomplicated gonorrhea. RESULTS: A total of 59 participants were enrolled and treated in this trial; 28 participants received 1200 mg of solithromycin and 31 received 1000 mg. Forty-six (78%) participants had positive cultures for N. gonorrhoeae at the time of enrollment: 24 of the 28 persons (86%) who received 1200 mg of oral solithromycin, and 22 of 31 (71%) who received 1000 mg. In addition, 8 participants had positive pharyngeal gonococcal cultures, and 4 had positive rectal cultures. All patients with positive cultures for N. gonorrhoeae were cured at all sites of infection. Chlamydia trachomatis and Mycoplasma genitalium coinfections were evaluated using nucleic acid amplification tests and were negative at 1 week of follow-up in 9 of 11 (82%) participants positive for C. trachomatis and 7 of 10 (70%) participants positive for M. genitalium. Mild dose-related gastrointestinal side effects (nausea, loose stools, vomiting) were common but did not limit therapy. CONCLUSIONS: Oral single-dose solithromycin, in doses of 1000 mg and 1200 mg, was 100% effective for treatment of culture-proven gonorrhea at genital, oral, and rectal sites of infection and is a promising new agent for gonorrhea treatment. CLINICAL TRIALS REGISTRATION: NCT01591447.
Assuntos
Antibacterianos , Gonorreia/tratamento farmacológico , Macrolídeos , Triazóis , Administração Oral , Adulto , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Farmacorresistência Bacteriana , Feminino , Gonorreia/microbiologia , Humanos , Macrolídeos/administração & dosagem , Macrolídeos/efeitos adversos , Macrolídeos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Neisseria gonorrhoeae/efeitos dos fármacos , Triazóis/administração & dosagem , Triazóis/efeitos adversos , Triazóis/uso terapêutico , Adulto JovemRESUMO
Solithromycin, a new macrolide and the first fluoroketolide, is in late-stage clinical development and, like older macrolides, is primarily metabolized and excreted through liver-dependent mechanisms. This study evaluated the safety and pharmacokinetics of solithromycin in patients with chronic liver disease. This open-label, multiple-dose study in subjects with hepatic impairment and in healthy control subjects (matched for age, weight, and sex) enrolled 8 Child-Pugh class A (mild), 8 class B (moderate), and 8 class C (severe) patients and 9 healthy controls. Subjects (n = 33) received one 800-mg dose on day 1 followed by once-daily doses of 400 mg on days 2 through 5. The most commonly reported adverse events were mild diarrhea and mild headache, and no significant differences were noted between hepatically impaired subjects and healthy controls. The pharmacokinetics of plasma solithromycin in subjects with mild and moderate impairment was similar to that in control subjects. In subjects with severe impairment, total exposure to solithromycin at steady state (area under the plasma concentration-time curve [AUC0-tau]) was decreased compared to that in control subjects, which may have been related to the higher body mass index of individuals in this group. No greater accumulation was noted in any hepatically impaired cohort on day 5 compared to that in control subjects. No decrease in dosage is therefore needed when administering solithromycin to patients with mild, moderate, or severe hepatic impairment. Solithromycin was well tolerated in this patient population, and no significant differences in safety, compared to healthy controls, were noted.
Assuntos
Hepatopatias/tratamento farmacológico , Macrolídeos/efeitos adversos , Macrolídeos/farmacocinética , Triazóis/efeitos adversos , Triazóis/farmacocinética , Adulto , Idoso , Área Sob a Curva , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hepatopatias/metabolismo , Masculino , Pessoa de Meia-IdadeRESUMO
The activity of solithromycin was evaluated against clinical Legionella pneumophila serogroup 1 (Lp1) isolates (n = 196) collected in Ontario, Canada, from 1980 to 2011. Its in vitro activity was compared to that of azithromycin (AZM) using the broth microdilution method. Solithromycin had a MIC50 of ≤0.015 µg/ml and a MIC90 of 0.031 µg/ml, making its activity at least 8-fold to 32-fold higher than that of AZM (MIC50 and MIC90, 0.125 µg/ml and 1 µg/ml, respectively). Ninety-nine percent of the isolates had MICs for solithromycin ranging from ≤0.015 µg/ml to 0.031 µg/ml, whereas 83.6% of the isolates showed MICs for AZM ranging from 0.062 µg/ml to 0.25 µg/ml. Interestingly, 96.7% (30 out of 31 clinical isolates) identified with higher AZM MICs (0.5 µg/ml to 2 µg/ml) belonged to the clinically prevalent sequence type 1. To investigate the intracellular activity of solithromycin, in vitro invasion assays were also performed against a subset of representative Lp1 isolates internalized within human lung epithelial cells. Solithromycin and AZM both inhibited growth of all intracellular Lp1 isolates at 1× or 8× MICs, displaying bacteriostatic effects, as would be expected with protein synthesis inhibitor rather than bactericidal activity. Solithromycin demonstrated the highest in vitro and intracellular potency against all Lp1 isolates compared to AZM. Given the rapid spread of resistance mechanisms among respiratory pathogens and the reported treatment failures in legionellosis, the development of this new fluoroketolide, already in phase 3 oral clinical studies, constitutes a promising alternative option for the treatment of legionellosis.
Assuntos
Antibacterianos/farmacologia , Legionella pneumophila/efeitos dos fármacos , Macrolídeos/farmacologia , Triazóis/farmacologia , Azitromicina/farmacologia , Linhagem Celular Tumoral , Ensaios Clínicos Fase III como Assunto , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/microbiologia , Humanos , Legionella pneumophila/classificação , Legionella pneumophila/crescimento & desenvolvimento , Legionella pneumophila/isolamento & purificação , Doença dos Legionários/tratamento farmacológico , Doença dos Legionários/microbiologia , Testes de Sensibilidade Microbiana , SorotipagemRESUMO
Mycoplasma genitalium has become well established as an etiological agent of sexually transmitted infections, but due to its fastidious growth requirements, only a few M. genitalium strains are available to determine the MICs of currently used and new antimicrobial agents. Recent clinical trials have suggested that treatment with azithromycin has decreasing efficacy due to an increasing prevalence of macrolide resistance, and alternative treatment with moxifloxacin is similarly under pressure from emerging resistance. Thus, there is an urgent need for new antimicrobials. The in vitro activity of the newly developed fluoroketolide solithromycin (CEM-101) was evaluated against a collection of 40 M. genitalium strains, including 15 with high-level macrolide resistance and 5 multidrug-resistant strains with resistance to both macrolides and quinolones. Furthermore, the MIC of solithromycin was correlated with mutations in the 23S rRNA gene and in the genes encoding ribosomal proteins L4 and L22. The in vitro results showed that solithromycin has activity against M. genitalium superior to that of other macrolides, doxycycline, and fluoroquinolones. Accordingly, this new fluoroketolide might be an effective option for treatment of M. genitalium infections. However, the efficacy of solithromycin in clinical trials with follow-up for test of cure and detection of genotypic and phenotypic resistance needs to be evaluated prior to widespread use. In a phase 2 clinical trial, solithromycin was highly effective as a single oral dose against C. trachomatis and Neisseria gonorrhoeae, suggesting that solithromycin could be a treatment option for several sexually transmitted infections, including in syndromic treatment of urethral and vaginal discharge.
Assuntos
Antibacterianos/farmacologia , Gonorreia/tratamento farmacológico , Macrolídeos/farmacologia , Infecções por Mycoplasma/tratamento farmacológico , Mycoplasma genitalium/efeitos dos fármacos , Triazóis/farmacologia , Azitromicina/farmacologia , DNA Bacteriano/química , DNA Bacteriano/genética , DNA Ribossômico/química , DNA Ribossômico/genética , Doxiciclina/farmacologia , Farmacorresistência Bacteriana , Fluoroquinolonas/farmacologia , Gonorreia/microbiologia , Humanos , Testes de Sensibilidade Microbiana , Moxifloxacina , Mutação , Infecções por Mycoplasma/microbiologia , Mycoplasma genitalium/genética , Neisseria gonorrhoeae/efeitos dos fármacosRESUMO
The in vitro antibacterial activity of solithromycin (CEM-101) against macrolide-resistant isolates (n=62) of Streptococcus agalactiae (group B streptococcus [GBS]) was determined. Phenotypic characterization of macrolide-resistant strains was performed by double-disc diffusion testing. A multiplex PCR was used to identify the erm(B), erm(TR), and mef(A/E) genes, capsular genotypes, and alpha-like (Alp) protein genes from the GBS strains. Determination of MIC was carried out using the microdilution broth method. The Etest method was used for penicillin, azithromycin, clarithromycin, and erythromycin. Solithromycin had a MIC50 of ≤0.008 µg/ml and a MIC90 of 0.015 µg/ml against macrolide-susceptible S. agalactiae. These MICs were lower than those displayed by penicillin (MIC50 of 0.032 µg/ml and MIC90 of 0.047 µg/ml), the antibiotic agent of choice for prophylaxis and treatment of GBS infections. Against macrolide-resistant S. agalactiae, solithromycin had a MIC50 of 0.03 µg/ml and a MIC90 of 0.125 µg/ml. Against erm(B) strains, solithromycin had a MIC50 of 0.03 µg/ml and a MIC90 of 0.06 µg/ml, while against mef(A) strains, it had a MIC50 of 0.03 µg/ml and a MIC90 of 0.125 µg/ml. Most erythromycin-resistant GBS strains were of serotype V (64.5%) and associated significantly with alp2-3. Moreover, a statistically significant association was observed between the constitutive macrolide-lincosamide-streptogramin B resistance (cMLSB) phenotype and the erm(B) gene-carrying strains, the alp2-3 gene and the M phenotype, and the mef(A/E) gene and epsilon. Overall, our results show that solithromycin had lower or similar MICs than penicillin and potent activity against macrolide-resistant strains independent of their genotype or phenotype, representing a valid therapeutic alternative where ß-lactams cannot be used.
Assuntos
Antibacterianos/farmacologia , Eritromicina/farmacologia , Macrolídeos/farmacologia , Streptococcus agalactiae/efeitos dos fármacos , Triazóis/farmacologia , Testes de Sensibilidade a Antimicrobianos por Disco-Difusão , Farmacorresistência Bacteriana , Genes Bacterianos/genética , Técnicas In Vitro , Testes de Sensibilidade Microbiana , Reação em Cadeia da Polimerase Multiplex , Streptococcus agalactiae/genéticaRESUMO
Solithromycin (CEM-101) is a new antibiotic that is highly potent against Ureaplasma and Mycoplasma spp. and active against many other antibiotic-resistant organisms. We have explored the maternal-amniotic-fetal pharmacokinetics of CEM-101 in a pregnant sheep model to assess its potential for treating intrauterine and antenatal infection. Chronically catheterized pregnant ewes (n = 6 or 7) received either a single maternal intravenous (i.v.) infusion of CEM-101 (10 mg/kg of body weight), a single intra-amniotic (i.a.) injection (1.4 mg/kg of estimated fetal weight), or a combined i.v. and i.a. dose. Maternal plasma (MP), fetal plasma (FP), and amniotic fluid (AF) samples were taken via catheter at intervals of 0 to 72 h postadministration, and concentrations of solithromycin and its bioactive polar metabolites (N-acetyl [NAc]-CEM-101 and CEM-214) were determined. Following maternal i.v. infusion, peak CEM-101 concentrations in MP, FP, and AF were 1,073, 353, and 214 ng/ml, respectively, representing a maternal-to-fetal plasma transfer efficiency of 34%. A single maternal dose resulted in effective concentrations (>30 ng/ml) in MP, FP, and AF sustained for >12 h. NAc-CEM-101 and CEM-214 exhibited delayed accumulation and clearance in FP and AF, resulting in an additive antimicrobial effect (>48 h). Intra-amniotic solithromycin injection resulted in elevated (â¼50 µg/ml) and sustained CEM-101 concentrations in AF and significant levels in FP, although the efficiency of amniotic-to-fetal transfer was low (â¼1.5%). Combined i.v. and i.a. administration resulted in primarily additive concentrations of CEM-101 in all three compartments. Our findings suggest that CEM-101 may provide, for the first time, an effective antimicrobial approach for the prevention and treatment of intrauterine infection and early prevention of preterm birth.
Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Feto/metabolismo , Macrolídeos/administração & dosagem , Macrolídeos/farmacocinética , Triazóis/administração & dosagem , Triazóis/farmacocinética , Líquido Amniótico/metabolismo , Animais , Antibacterianos/uso terapêutico , Feminino , Humanos , Macrolídeos/uso terapêutico , Gravidez , Ovinos , Triazóis/uso terapêuticoRESUMO
We evaluated the activity of solithromycin against 196 clinical gonococcal isolates collected at the Public Health Ontario Laboratories, Toronto, Canada, including isolates with different levels of azithromycin resistance, as well as the role of pH in MIC determinations using pH-adjusted agar plates (pH range, 5.6 to 7.6). In vitro invasion assays were performed using monolayers of HeLa epithelial cells and clinical gonococci displaying different azithromycin MICs; infected cultures were treated with solithromycin, and its intracellular activity was determined by CFU assays after 3 and 20 h of exposure. Solithromycin displayed a MIC50 and MIC90 of 0.0625 and 0.125 µg/ml, respectively, making its activity at least 4-fold higher than that of azithromycin. Clinical isolates with elevated MICs for azithromycin (MICs of ≥2,048 µg/ml and 4 to 8 µg/ml) showed solithromycin MIC values of 8 and 0.5 µg/ml, respectively. In contrast to azithromycin, solithromycin MICs were not significantly affected by acidic pHs, suggesting more stability at lower pH. Moreover, when intracellular Neisseria gonorrhoeae isolates were incubated with solithromycin at 4 times, 1 times, and one-fourth of the MIC, the exposure to solithromycin resulted in the progressive loss of viability of most isolates over time. The intracellular activity of solithromycin, combined with the low MICs to this agent, indicates that it may be an attractive option for gonorrhea treatment if clinical trials in development reveal that this drug can be used safely in adult indications, especially when multidrug-resistant clinical isolates are now emerging.