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Current Opinion in Microbiology Apr 2023Streptococcus pneumoniae is the most common cause of community-acquired pneumonia, and one of the main pathogens responsible for otitis media infections in children.... (Review)
Review
Streptococcus pneumoniae is the most common cause of community-acquired pneumonia, and one of the main pathogens responsible for otitis media infections in children. Amoxicillin (AMX) is a broad-spectrum β-lactam antibiotic, used frequently for the treatment of bacterial respiratory tract infections. Here, we discuss the pneumococcal response to AMX, including the mode of action of AMX, the effects on autolysin regulation, and the evolution of resistance through natural transformation. We discuss current knowledge gaps in the synthesis and translocation of peptidoglycan and teichoic acids, major constituents of the pneumococcal cell wall and critical to AMX activity. Furthermore, an outlook of AMX resistance research is presented, including the development of natural competence inhibitors to block evolution via horizontal gene transfer, and the use of high-throughput essentiality screens for the discovery of novel cotherapeutics.
Topics: Child; Humans; Amoxicillin; Streptococcus pneumoniae; Respiratory Tract Infections; Peptidoglycan; Biology; Anti-Bacterial Agents
PubMed: 36638546
DOI: 10.1016/j.mib.2022.102261 -
MBio Feb 2022Mycobacterium abscessus () infections are a growing menace to the health of many patients, especially those suffering from structural lung disease and cystic fibrosis....
Mycobacterium abscessus () infections are a growing menace to the health of many patients, especially those suffering from structural lung disease and cystic fibrosis. With multidrug resistance a common feature and a growing understanding of peptidoglycan synthesis in , it is advantageous to identify potent β-lactam and β-lactamase inhibitor combinations that can effectively disrupt cell wall synthesis. To improve existing therapeutic regimens to address serious infections, we evaluated the ability of durlobactam (DUR), a novel diazobicyclooctane β-lactamase inhibitor to restore susceptibilities in combination with β-lactams and provide a biochemical rationale for the activity of this compound. In cell-based assays, susceptibility of subsp. isolates to amoxicillin (AMOX), imipenem (IMI), and cefuroxime (CXM) was significantly enhanced with the addition of DUR. The triple drug combinations of CXM-DUR-AMOX and IMI-DUR-AMOX were most potent, with MIC ranges of ≤0.06 to 1 μg/mL and an MIC/MIC of ≤0.06/0.25 μg/mL, respectively. We propose a model by which this enhancement may occur, DUR potently inhibited the β-lactamase Bla with a relative Michaelis constant ( ) of 4 × 10 ± 0.8 × 10μM and acylation rate (/) of 1 × 10 M s. Timed mass spectrometry captured stable formation of carbamoyl-enzyme complexes between DUR and Ldt and d,d-carboxypeptidase, potentially contributing to the intrinsic activity of DUR. Molecular modeling showed unique and favorable interactions of DUR as a Bla inhibitor. Similarly, modeling showed how DUR might form stable Michaelis-Menten complexes with Ldt and d,d-carboxypeptidase. The ability of DUR combined with amoxicillin or cefuroxime and imipenem to inactivate multiple targets such as d,d-carboxypeptidase and Ldt supports new therapeutic approaches using β-lactams in eradicating . Durlobactam (DUR) is a potent inhibitor of Bla and provides protection of amoxicillin and imipenem against hydrolysis. DUR has intrinsic activity and forms stable acyl-enzyme complexes with Ldt and Ldt. The ability of DUR to protect amoxicillin and imipenem against Bla and its intrinsic activity along with the dual β-lactam target redundancy can explain the rationale behind the potent activity of this combination.
Topics: Humans; beta-Lactams; beta-Lactamase Inhibitors; Anti-Bacterial Agents; Mycobacterium abscessus; Cefuroxime; Microbial Sensitivity Tests; Imipenem; Amoxicillin; beta-Lactamases
PubMed: 35073757
DOI: 10.1128/mbio.03529-21 -
The American Journal of Tropical... Jun 2015Little is known about the quality of antibiotics despite being in high demand globally. Thirty five samples (27 brands) of the antibiotics amoxicillin (N = 20; 16...
Little is known about the quality of antibiotics despite being in high demand globally. Thirty five samples (27 brands) of the antibiotics amoxicillin (N = 20; 16 brands) and co-trimoxazole (N = 15; 11 brands), manufactured in six countries (China, Ghana, India, Ireland, Nigeria, and United Kingdom), were purchased in Ghana, Nigeria, and the United Kingdom. Their quality was assessed using German Pharma Health Fund (GPHF) MiniLab® as the screening tool-two capsules of amoxicillin (10%) and two tablets of co-trimoxazole (20%) failed the thin-layer chromatography (TLC) test. Definitive drug quality was measured using high-performance liquid chromatography-photodiode array detection (HPLC-PDA) for content of the stated active pharmaceutical ingredients (APIs) and bioavailability was determined with in vitro dissolution testing. All the samples of amoxicillin complied with U.S. Pharmacopeia (USP) tolerance limits, but 60% tablets of co-trimoxazole (purchased in Ghana and Nigeria) did not. There was disparity in the results obtained for co-trimoxazole and amoxicillin samples using the MiniLab® TLC tests. This highlights the need to invest in techniques such as HPLC-PDA and dissolution testing alongside the screening tests for assessing drug quality.
Topics: Amoxicillin; Anti-Bacterial Agents; Chemistry Techniques, Analytical; Counterfeit Drugs; Ghana; Nigeria; Quality Control; Sensitivity and Specificity; Trimethoprim, Sulfamethoxazole Drug Combination; United Kingdom
PubMed: 25897067
DOI: 10.4269/ajtmh.14-0539 -
European Journal of Pharmaceutical... Oct 2023This study aimed to assess the pharmacokinetic (PK) interactions of anaprazole, clarithromycin, and amoxicillin using physiologically based pharmacokinetic (PBPK) models.
Physiologically based pharmacokinetic modeling to assess the drug-drug interactions of anaprazole with clarithromycin and amoxicillin in patients undergoing eradication therapy of H. pylori infection.
OBJECTIVE
This study aimed to assess the pharmacokinetic (PK) interactions of anaprazole, clarithromycin, and amoxicillin using physiologically based pharmacokinetic (PBPK) models.
METHODS
The PBPK models for anaprazole, clarithromycin, and amoxicillin were constructed using the GastroPlus™ software (Version 9.7) based on the physicochemical data and PK parameters obtained from literature, then were optimized and validated in healthy subjects to predict the plasma concentration-time profiles of these three drugs and assess the predictive performance of each model. According to the analysis of the properties of each drug, the developed and validated models were applied to evaluate potential drug-drug interactions (DDIs) of anaprazole, clarithromycin, and amoxicillin.
RESULTS
The developed PBPK models properly described the pharmacokinetics of anaprazole, clarithromycin, and amoxicillin well, and all predicted PK parameters (C, AUC ratios were within 2.0-fold of the observed values. Furthermore, the application of these models to predict the anaprazole-clarithromycin and anaprazole-amoxicillin DDIs demonstrates their good performance, with the predicted DDI C ratios and DDI AUC ratios within 1.25-fold of the observed values, and all predicted DDI C, and AUC ratios within 2.0-fold. The simulated results show no need to adjust the dosage when co-administered with anaprazole in patients undergoing eradication therapy of H. pylori infection since the dose remained in the therapeutic range.
CONCLUSION
The whole-body PBPK models of anaprazole, clarithromycin, and amoxicillin were built and qualified, which can predict DDIs that are mediated by gastric pH change and inhibition of metabolic enzymes, providing a mechanistic understanding of the DDIs observed in the clinic of clarithromycin, amoxicillin with anaprazole.
Topics: Humans; Clarithromycin; Amoxicillin; Helicobacter pylori; Helicobacter Infections; Drug Interactions; Models, Biological
PubMed: 37480962
DOI: 10.1016/j.ejps.2023.106534 -
Archives of Razi Institute Aug 2023() is considered a challenging type of bacteria that is difficult to treat with the currently used antibiotics, such as amoxicillin, erythromycin, and metronidazole,...
() is considered a challenging type of bacteria that is difficult to treat with the currently used antibiotics, such as amoxicillin, erythromycin, and metronidazole, which have proven ineffective against these bacteria. In this study, modern technology was used to treat these bacteria by converting the aforementioned antibiotics to their nano state using the lyophilization method and diagnosing them using scanning electron microscopy. A mixture of the three nano-antibiotics was prepared in the form of a nano-medicine, which was used to treat bacteria in cultures and determine the effectiveness of nano-antibiotics and nano-medicine on these bacteria. The findings showed that nano-medicine was highly effective in inhibiting these bacteria at the lowest concentration (OD=0.042) and the highest concentration (OD=0.038), compared to the three micro-antibiotics individually. The OD values of amoxicillin, azithromycin, and metronidazole were 0.523, 0.521, and 0.453, respectively. The OD values of the three nano-antibiotics, including nano-amoxicillin, nano-azithromycin, and nano-metronidazole, were 0.386, 0.258, and 0.167, respectively. It was observed that the percentage of inhibition in each of the nano-antibiotics was higher than the inhibition in micro-antibiotics and that the nano-medicine had much higher inhibition than each of the three micro- and nano-antibiotics alike. The safety of using nano-antibiotics in the prepared medicine was confirmed using electrochemical technology and cyclic voltammetry to identify the electrochemical properties through oxidation and reduction in blood media. Based on the findings, only reduction peaks appeared, and there were no oxidation peaks in the prepared kit or for each of the three nano-antibiotics. It was found that they were all non-oxidants and could be used safely as good antioxidants in treatments. However, the same three micro treatments showed blood oxidation due to the appearance of oxidation peaks in all of them. The study proved that all isolates are resistant to usable antibiotics. All of the antibiotics in the nano-medicine had an anti-bacterial effect, and the effect of the new form of antibiotic was proportional to the concentration of the antibiotic.
Topics: Animals; Helicobacter Infections; Metronidazole; Helicobacter pylori; Anti-Bacterial Agents; Amoxicillin; Azithromycin
PubMed: 38226381
DOI: 10.32592/ARI.2023.78.4.1313 -
Saudi Journal of Gastroenterology :... 2023Vonoprazan-amoxicillin (VA) dual therapy has recently been proposed to eradicate Helicobacter pylori (H. pylori) with controversial results. We, therefore, conducted a... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Vonoprazan-amoxicillin (VA) dual therapy has recently been proposed to eradicate Helicobacter pylori (H. pylori) with controversial results. We, therefore, conducted a meta-analysis to assess the effect of this therapy for H. pylori eradication.
METHODS
We searched PubMed, Embase, Cochrane Library, and Web of Science database from inception until November 2022, collecting randomized controlled trials (RCTs) comparing VA dual therapy with other regimens for H. pylori eradication. Pooled relative risks (RRs) were calculated using random effects model.
RESULTS
Five RCTs were ultimately included. Compared with the vonoprazan-amoxicillin-clarithromycin (VAC) triple therapy, the eradication rate of VA dual therapy was lower in intention-to-treat (ITT) analysis (n = 3 RCTs, RR = 0.94, 95% CI: 0.88-0.99, P = 0.03), but there was no significant difference between them in the per-protocol (PP) analysis (RR = 0.96, 95% CI: 0.91-1.01, P = 0.11). For clarithromycin-resistant H. pylori strains, the eradication rate of VA dual therapy was significantly higher than that of the VAC triple therapy (n = 2 RCTs, RR = 1.20, 95% CI: 1.03-1.39, P = 0.02). Compared with the PPI-based triple therapy (PAC), VA dual therapy had a superior eradication rate (n = 2 RCTs, ITT analysis: RR = 1.13, 95% CI: 1.04-1.23, P = 0.003; PP analysis: pooled RR = 1.14, 95% CI: 1.06-1.22, P = 0.0004). Compared with VAC or PAC triple therapy, VA dual therapy has a similar incidence of total adverse events and compliance.
CONCLUSIONS
VA dual therapy had a similar effect compared to VAC triple therapy and was superior to PAC triple therapy. Future RCTs are needed to ascertain the optimal dosage and duration of vonoprazan and amoxicillin, and the effect of VA dual therapy compared with the mainstream regimens recommended by current guidelines.
Topics: Humans; Amoxicillin; Clarithromycin; Anti-Bacterial Agents; Helicobacter pylori; Helicobacter Infections; Proton Pump Inhibitors; Randomized Controlled Trials as Topic; Drug Therapy, Combination; Treatment Outcome
PubMed: 37602635
DOI: 10.4103/sjg.sjg_153_23 -
The Cochrane Database of Systematic... Mar 2015Acute lower respiratory tract infections (LRTI) range from acute bronchitis and acute exacerbations of chronic bronchitis to pneumonia. Approximately five million people... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Acute lower respiratory tract infections (LRTI) range from acute bronchitis and acute exacerbations of chronic bronchitis to pneumonia. Approximately five million people die from acute respiratory tract infections annually. Among these, pneumonia represents the most frequent cause of mortality, hospitalisation and medical consultation. Azithromycin is a macrolide antibiotic, structurally modified from erythromycin and noted for its activity against some gram-negative organisms associated with respiratory tract infections, particularly Haemophilus influenzae (H. influenzae).
OBJECTIVES
To compare the effectiveness of azithromycin to amoxycillin or amoxycillin/clavulanic acid (amoxyclav) in the treatment of LRTI, in terms of clinical failure, incidence of adverse events and microbial eradication.
SEARCH METHODS
We searched CENTRAL (2014, Issue 10), MEDLINE (January 1966 to October week 4, 2014) and EMBASE (January 1974 to November 2014).
SELECTION CRITERIA
Randomised controlled trials (RCTs) and quasi-RCTs, comparing azithromycin to amoxycillin or amoxycillin/clavulanic acid in participants with clinical evidence of an acute LRTI, such as acute bronchitis, pneumonia and acute exacerbation of chronic bronchitis.
DATA COLLECTION AND ANALYSIS
The review authors independently assessed all potential studies identified from the searches for methodological quality. We extracted and analysed relevant data separately. We resolved discrepancies through discussion. We initially pooled all types of acute LRTI in the meta-analyses. We investigated the heterogeneity of results using the forest plot and Chi(2) test. We also used the index of the I(2) statistic to measure inconsistent results among trials. We conducted subgroup and sensitivity analyses.
MAIN RESULTS
We included 16 trials involving 2648 participants. We were able to analyse 15 of the trials with 2496 participants. The pooled analysis of all the trials showed that there was no significant difference in the incidence of clinical failure on about days 10 to 14 between the two groups (risk ratio (RR), random-effects 1.09; 95% confidence interval (CI) 0.64 to 1.85). A subgroup analysis in trials with acute bronchitis participants showed significantly lower clinical failure in the azithromycin group compared to amoxycillin or amoxyclav (RR random-effects 0.63; 95% CI 0.45 to 0.88). A sensitivity analysis showed a non-significant reduction in clinical failure in azithromycin-treated participants (RR 0.55; 95% CI 0.25 to 1.21) in three adequately concealed studies, compared to RR 1.32; 95% CI 0.70 to 2.49 in 12 studies with inadequate concealment. Twelve trials reported the incidence of microbial eradication and there was no significant difference between the two groups (RR 0.95; 95% CI 0.87 to 1.03). The reduction of adverse events in the azithromycin group was RR 0.76 (95% CI 0.57 to 1.00).
AUTHORS' CONCLUSIONS
There is unclear evidence that azithromycin is superior to amoxycillin or amoxyclav in treating acute LRTI. In patients with acute bronchitis of a suspected bacterial cause, azithromycin tends to be more effective in terms of lower incidence of treatment failure and adverse events than amoxycillin or amoxyclav. However, most studies were of unclear methodological quality and had small sample sizes; future trials of high methodological quality and adequate sizes are needed.
Topics: Acute Disease; Amoxicillin; Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Azithromycin; Bronchitis; Drug Therapy, Combination; Humans; Pneumonia; Randomized Controlled Trials as Topic; Respiratory Tract Infections; Treatment Failure
PubMed: 25749735
DOI: 10.1002/14651858.CD001954.pub4 -
Gut Jun 2020To date, no randomised trials have compared the efficacy of vonoprazan and amoxicillin dual therapy with other standard regimens for treatment. This study aimed to... (Comparative Study)
Comparative Study
OBJECTIVE
To date, no randomised trials have compared the efficacy of vonoprazan and amoxicillin dual therapy with other standard regimens for treatment. This study aimed to investigate the efficacy of the 7-day vonoprazan and low-dose amoxicillin dual therapy as a first-line treatment, and compared this with vonoprazan-based triple therapy.
DESIGN
This prospective, randomised clinical trial was performed at seven Japanese institutions. Patients with -positive culture test and naive to treatment were randomly assigned in a 1:1 ratio to either VA-dual therapy (vonoprazan 20 mg+amoxicillin 750 mg twice/day) or VAC-triple therapy (vonoprazan 20 mg+amoxicillin 750 mg+clarithromycin 200 mg twice/day) for 7 days, with stratification by age, sex, antimicrobial resistance and institution. Eradication success was evaluated by C-urea breath test at least 4 weeks after treatment.
RESULTS
Between October 2018 and June 2019, 629 subjects were screened and 335 were randomised. The eradication rates of VA-dual and VAC-triple therapies were 84.5% and 89.2% (p=0.203) by intention-to-treat analysis, respectively, and 87.1% and 90.2% (p=0.372) by per-protocol analysis, respectively. VA-dual was non-inferior to VAC-triple in the per-protocol analysis. The eradication rates in strains resistant to clarithromycin for VA-dual were significantly higher than those for VAC-triple (92.3% vs 76.2%; p=0.048). The incidence of adverse events was equal between groups.
CONCLUSION
The 7-day vonoprazan and low-dose amoxicillin dual therapy provided acceptable eradication rates and a similar effect to vonoprazan-based triple therapy in regions with high clarithromycin resistance.
TRIAL REGISTRATION NUMBER
UMIN000034140.
Topics: Adult; Aged; Amoxicillin; Anti-Bacterial Agents; Clarithromycin; Drug Administration Schedule; Drug Therapy, Combination; Female; Helicobacter Infections; Helicobacter pylori; Humans; Male; Middle Aged; Pyrroles; Sulfonamides
PubMed: 31915235
DOI: 10.1136/gutjnl-2019-319954 -
PloS One 2022Polypharmacy may be considered as the customary practice to provide optimum care services to patients but inter resulted in augmented probability of multiple drug... (Randomized Controlled Trial)
Randomized Controlled Trial
Polypharmacy may be considered as the customary practice to provide optimum care services to patients but inter resulted in augmented probability of multiple drug interaction. Keeping in view the importance of drug interaction possibility, this study was designed to evaluate the effect of ranitidine on pharmacokinetics of amoxicillin in the local population of Karachi, Pakistan. Amoxicillin and ranitidine are the most commonly prescribed drugs to treat duodenal ulcer caused by Helicobacter pylori. The current investigation was carried out as a single center, open label, two phase, single dose, randomized way in cross over manner to evaluate the potential of pharmacokinetic interaction among amoxicillin formulation and ranitidine in adult healthy male volunteers. Post dosing blood samples were collected at multiple time points that are 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 10 hours after administering amoxicillin 250mg capsule with and without ranitidine. For estimation of amoxicillin concentration in plasma, an HPLC method was developed and validated. The solvent system consisted of 0.025M phosphate buffer: acetonitrile (94:6 v/v). C18 column was employed with a flow rate of 1.0 ml/minute and at 230nm. A linear pattern with a correlation coefficient of 0.999 in the concentration ranges of 25μg/mL to 0.097μg/mL for amoxicillin and 25μg/mL to 0.048μg/mL for ranitidine was observed. Amoxicillin retention time was about 8 minutes and ranitidine retention time was around 12 minutes. Amoxicillin levels were computed and the concentrations were applied to calculate the pharmacokinetic parameters. Pharmacokinetic parameters were estimated by Kinetica TM 4.4.1 (Thermo Electron Corp. USA). The analysis of variance (two way) and t test (two one sided) were applied on log transformed pharmacokinetic parameters of amoxicillin. The Tmax was determined between amoxicillin alone and amoxicillin with ranitidine by Friedman test. The 90% confidence interval values for Cmax(calc) (0.687-0.743) and Tmax(calc) (1.148-1.742) for amoxicillin with or without ranitidine were not found within the FDA acceptable limits of 0.8-1.25. Study demonstrated the significant reduction in peak plasma levels of amoxicillin in presence of ranitidine. It is advisable to administer both drugs with time interval to avoid such interactions and increases in the bactericidal efficacy of amoxicillin.
Topics: Adult; Amoxicillin; Anti-Bacterial Agents; Healthy Volunteers; Helicobacter Infections; Helicobacter pylori; Humans; Male; Pakistan; Ranitidine
PubMed: 35609024
DOI: 10.1371/journal.pone.0267791 -
Journal of Korean Medical Science Sep 2023The lack of well-established operational definitions is a major limitation of eradication studies that use secondary databases. We aimed to develop and validate...
BACKGROUND
The lack of well-established operational definitions is a major limitation of eradication studies that use secondary databases. We aimed to develop and validate operational definitions related to eradication therapy.
METHODS
Operational definitions were developed by analyzing a nationwide eradication registry and validated using real-world data from hospital medical records. The primary endpoint was the sensitivity of the operational definitions in identifying individuals who received eradication therapy. The secondary endpoint was the sensitivity and specificity of the operational definition in identifying successful eradication therapy.
RESULTS
eradication therapy was defined as a prescription for one of the following combinations: 1) proton pump inhibitor (PPI) + amoxicillin + clarithromycin, 2) PPI + amoxicillin + metronidazole, 3) PPI + metronidazole + tetracycline, 4) PPI + amoxicillin + levofloxacin, 5) PPI + amoxicillin + moxifloxacin, or 6) PPI + amoxicillin + rifabutin. In the validation set, the sensitivity of the operational definition for identifying individuals who received eradication therapy was 99.7% and 99.8% for the first- and second-line therapies, respectively. Operational definition to determine success or failure of the eradication therapy was developed based on a confirmatory test and the prescription of rescue therapy. The sensitivity and specificity of the operational definition for predicting successful eradication were 97.6% and 91.4%, respectively, in first-line therapy and 98.6% and 54.8%, respectively, in second-line therapy.
CONCLUSION
We developed and validated operational definitions related to eradication therapy. These definitions will help researchers perform various eradication-related studies using secondary databases.
Topics: Humans; Helicobacter pylori; Metronidazole; Research Design; Anti-Bacterial Agents; Amoxicillin; Proton Pump Inhibitors
PubMed: 37667583
DOI: 10.3346/jkms.2023.38.e278