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British Journal of Clinical Pharmacology Aug 2017In vitro studies have demonstrated that formation of reactive oxygen species (ROS) contributes to the effect of bactericidal antibiotics. The formation of ROS is not... (Randomized Controlled Trial)
Randomized Controlled Trial
AIMS
In vitro studies have demonstrated that formation of reactive oxygen species (ROS) contributes to the effect of bactericidal antibiotics. The formation of ROS is not restricted to bacteria, but also occurs in mammalian cells. Oxidative stress is linked to several diseases. This study investigates whether antibiotic drugs induce oxidative stress in healthy humans as a possible mechanism for adverse reactions to the antibiotic drugs.
METHODS
This study contains information from two randomised, controlled trials. Participants underwent 1 week treatment with clarithromycin, trimethoprim, phenoxymethylpenicillin (penicillin V), or placebo. Oxidative modifications were measured as 24-h urinary excretion of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) and 8-oxo-7,8-dihydroguanosine (8-oxoGuo), and plasma levels of malondialdehyde before and after treatment as a measurement of DNA oxidation, RNA oxidation, and lipid peroxidation, respectively.
RESULTS
Clarithromycin significantly increased urinary excretion of 8-oxodG by 22.0% (95% confidence interval (CI): 3.6-40.4%) and 8-oxoGuo by 14.9% (95% CI: 3.7-26.1%). Further, we demonstrated that trimethoprim significantly lowered urinary excretion of 8-oxodG by 21.7% (95% CI: 5.8-37.6%), but did not influence urinary excretion of 8-oxoGuo. Penicillin V did not influence urinary excretion of 8-oxodG or 8-oxoGuo. None of the antibiotic drugs influenced plasma levels of malondialdehyde.
CONCLUSION
Clarithromycin significantly increases oxidative nucleic acid modifications. Increased oxidative modifications might explain some of clarithromycin's known adverse reactions. Trimethoprim significantly lowers DNA oxidation but not RNA oxidation. Penicillin V had no effect on oxidative nucleic acid modifications.
Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Anti-Bacterial Agents; Biomarkers; Clarithromycin; DNA; Deoxyguanosine; Guanosine; Healthy Volunteers; Humans; Lipid Peroxidation; Male; Malondialdehyde; Oxidation-Reduction; Oxidative Stress; Penicillin V; Placebos; RNA; Reactive Oxygen Species; Trimethoprim; Young Adult
PubMed: 28185274
DOI: 10.1111/bcp.13261 -
Antimicrobial Agents and Chemotherapy Feb 1990A regimen of a single intramuscular dose of penicillin G-streptomycin was compared with regimens of three oral doses of amoxicillin and two oral doses of penicillin V to...
Tolerance and efficacy of parenterally administered penicillin-streptomycin and orally administered amoxicillin or penicillin V for prophylaxis of experimentally induced streptococcal endocarditis.
A regimen of a single intramuscular dose of penicillin G-streptomycin was compared with regimens of three oral doses of amoxicillin and two oral doses of penicillin V to prevent Streptococcus sanguis endocarditis in rabbits with experimentally induced valvular heart lesions. Challenge doses of 10(4), 10(6), and 10(8) CFU of a strain of S. sanguis highly tolerant to penicillin and amoxicillin were used. The combination of penicillin and streptomycin was the only regimen tested that provided full protection even against the highest inoculum concentration. A single oral dose of penicillin V (36 mg/kg) or amoxicillin (50 mg/kg), two oral doses of penicillin V (36 and 18 mg/kg with a 7-h interval between doses), or six oral doses of amoxicillin (50 mg/kg followed by 8.5 mg/kg at 8-h intervals) protected recipients of the lowest inoculum concentration; protection diminished with increasing inocula. In contrast, administration of two high oral doses of amoxicillin (50 mg/kg) with a 10-h interval between doses provided full protection against challenge doses of 10(4) and 10(6) CFU, preventing endocarditis in 10 (66%) of 15 recipients of 10(8) CFU. All regimens evaluated were highly effective in preventing endocarditis when rabbits were challenged with 10(4) CFU. The combination of penicillin and streptomycin was the best regimen tested. Administration of two high oral doses of amoxicillin (50 mg/kg) with a 10-h interval between doses led to significantly fewer infections when compared with the other oral regimens when rabbits were challenged with 10(6) and 10(8) CFU.
Topics: Amoxicillin; Animals; Drug Therapy, Combination; Endocarditis, Bacterial; Microbial Sensitivity Tests; Penicillin G; Penicillin V; Penicillins; Rabbits; Streptococcal Infections; Streptococcus sanguis; Streptomycin
PubMed: 2109579
DOI: 10.1128/AAC.34.2.321 -
The FEBS Journal Jun 2016Mycobacterium tuberculosis is a human respiratory pathogen that causes the deadly disease tuberculosis. The rapid global spread of antibiotic-resistant M. tuberculosis...
UNLABELLED
Mycobacterium tuberculosis is a human respiratory pathogen that causes the deadly disease tuberculosis. The rapid global spread of antibiotic-resistant M. tuberculosis makes tuberculosis infections difficult to treat. To overcome this problem new effective antimicrobial strategies are urgently needed. One promising target for new therapeutic approaches is PonA1, a class A penicillin-binding protein, which is required for maintaining physiological cell wall synthesis and cell shape during growth in mycobacteria. Here, crystal structures of the transpeptidase domain, the enzymatic domain responsible for penicillin binding, of PonA1 from M. tuberculosis in the inhibitor-free form and in complex with penicillin V are reported. We used site-directed mutagenesis, antibiotic profiling experiments, and fluorescence thermal shift assays to measure PonA1's sensitivity to different classes of β-lactams. Structural comparison of the PonA1 apo-form and the antibiotic-bound form shows that binding of penicillin V induces conformational changes in the position of the loop β4'-α3 surrounding the penicillin-binding site. We have also found that binding of different antibiotics including penicillin V positively impacts protein stability, while other tested β-lactams such as clavulanate or meropenem resulted in destabilization of PonA1. Our antibiotic profiling experiments indicate that the transpeptidase activity of PonA1 in both M. tuberculosis and M. smegmatis mediates tolerance to specific cell wall-targeting antibiotics, particularly to penicillin V and meropenem. Because M. tuberculosis is an important human pathogen, these structural data provide a template to design novel transpeptidase inhibitors to treat tuberculosis infections.
DATABASE
Structural data are available in the PDB database under the accession numbers 5CRF and 5CXW.
Topics: Binding Sites; Crystallography, X-Ray; Drug Resistance, Microbial; Humans; Mutagenesis, Site-Directed; Mycobacterium tuberculosis; Penicillin V; Penicillin-Binding Proteins; Peptidyl Transferases; Tuberculosis; beta-Lactams
PubMed: 27101811
DOI: 10.1111/febs.13738 -
Journal of Dental Research Sep 2019Dentists prescribe a large portion of all oral antibiotics, and these are associated with a risk of adverse drug reactions (ADRs). The aim of this study was to quantify...
Dentists prescribe a large portion of all oral antibiotics, and these are associated with a risk of adverse drug reactions (ADRs). The aim of this study was to quantify the risk of ADRs associated with oral antibiotics commonly prescribed by dentists. NHS Digital Prescribing data and Yellow Card Drug Analysis data for 2010 to 2017 were abstracted to quantify dental antibiotic prescribing in England, and the rate and types of ADRs associated with them. During the period of study, the mean number of actively practicing dentists in England was 23,624. Amoxicillin accounted for 64.8% of dental antibiotic prescribing and had the lowest reported rate of fatal ADRs (0.1/million prescriptions) and overall ADRs (21.5/million prescriptions). Indeed, amoxicillin was respectively 6 and 3 times less likely to cause an ADR than the other penicillins, penicillin V and amoxicillin + clavulanic acid, and appears to be very safe in patients with no history of penicillin allergy. In contrast, clindamycin, which is often used in patients with penicillin allergy, had the highest rate of fatal (2.9/million prescriptions) and overall (337.3/million prescriptions) ADRs, with (formerly ) infections pivotal to its ADR profile. Other amoxicillin alternatives, clarithromycin and metronidazole, while significantly worse than amoxicillin, were 3 and nearly 5 times less likely to cause an ADR than clindamycin. Ranked from least to most likely to cause an ADR, antibiotics most commonly prescribed were as follows: amoxicillin < cephalosporins < erythromycin < tetracyclines < azithromycin < metronidazole < amoxicillin + clavulanic acid < clarithromycin < penicillin V < clindamycin. This study confirmed the high level of safety associated with use of amoxicillin by dentists and the significantly worse rates of fatal and nonfatal ADRs associated with other penicillins and alternatives to amoxicillin for those who are penicillin allergic. In particular, clindamycin had the highest rate of fatal and nonfatal ADRs of any of the antibiotics commonly prescribed by dentists.
Topics: Administration, Oral; Adverse Drug Reaction Reporting Systems; Amoxicillin; Anti-Bacterial Agents; Clarithromycin; Clindamycin; Dentists; England; Humans; Metronidazole; Penicillins
PubMed: 31314998
DOI: 10.1177/0022034519863645 -
BMJ (Clinical Research Ed.) Feb 2016To evaluate if oral fluoroquinolone use is associated with an increased risk of serious arrhythmia.
OBJECTIVE
To evaluate if oral fluoroquinolone use is associated with an increased risk of serious arrhythmia.
DESIGN
Bi-national cohort study, linking register data on filled prescriptions, cases of serious arrhythmia, and patient characteristics.
SETTING
Denmark, 1997-2011; Sweden, 2006-13.
PARTICIPANTS
The study cohort was derived from a source population of all Danish and Swedish adults, aged 40 to 79 years. 909,656 courses of fluoroquinolone use (ciprofloxacin 82.6%, norfloxacin 12.1%, ofloxacin 3.2%, moxifloxacin 1.2%, and other fluoroquinolones 0.9%) and 909,656 courses of penicillin V use, matched 1:1 on propensity score, were included.
MAIN OUTCOME MEASURE
The main outcome was risk of serious arrhythmia (fatal and non-fatal), comparing courses of fluoroquinolone use with courses of penicillin V use (an antibiotic with no pro-arrhythmic effect). The risk period of interest was current use, defined as days 0-7 of treatment. Subgroup analyses were conducted according to country, sex, age, underlying cardiovascular disease, concomitant use of drugs known to increase the risk of torsades de pointes, fluoroquinolone type, and levels of arrhythmia risk score.
RESULTS
144 cases of serious arrhythmia occurred during follow-up, 66 among current fluoroquinolone users (incidence rate 3.4 per 1000 person years) and 78 among current penicillin users (4.0 per 1000 person years); comparing oral fluoroquinolone treatment with penicillin V, the rate ratio was 0.85 (95% confidence interval 0.61 to 1.18). Compared with penicillin V, the absolute risk difference was -13 (95% confidence interval -35 to 16) cases of serious arrhythmia per 1,000,000 courses of fluoroquinolones. The risk of serious arrhythmia was not statistically significantly increased in any of the subgroups, including analyses by fluoroquinolone type.
CONCLUSIONS
Contrary to previous reports, oral fluoroquinolone treatment was not associated with an increased risk of serious arrhythmia in the general adult populations of Denmark and Sweden. Given the statistical power of the study, even small increases in relative and absolute risk could be ruled out. Since ciprofloxacin was the most commonly used fluoroquinolone in our study, we cannot exclude that intraclass differences influence the risk of serious arrhythmia associated with other less frequently used fluoroquinolones.
Topics: Administration, Oral; Adult; Aged; Anti-Bacterial Agents; Arrhythmias, Cardiac; Denmark; Epidemiologic Methods; Fluoroquinolones; Humans; Middle Aged; Penicillin V; Sweden
PubMed: 26920666
DOI: 10.1136/bmj.i843 -
MSphere Jun 2018Various species have been reported to deconjugate bile acids in the gastrointestinal tract (GIT) through the action of bile salt hydrolase (BSH) proteins. This function...
Various species have been reported to deconjugate bile acids in the gastrointestinal tract (GIT) through the action of bile salt hydrolase (BSH) proteins. This function contributes to altering the gut microbiota composition and bile metabolism and detoxification and to lowering cholesterol levels. Here, we investigated the BSH repertoire across 170 sequenced species. We used hidden Markov models to distinguish between BSH and closely related penicillin-V acylase (PVA) proteins. Even though BSH and PVA proteins have very different target substrates, they share high sequence similarity and are often misannotated. We determined that 82/170 (48.24%) species encoded PVA proteins, 39/170 (22.94%) species encoded BSH proteins, and 8/170 (4.71%) species encoded both BSH and PVA proteins, while 57/170 (33.53%) species encoded neither. Mapping the occurrence of BSH-encoding species onto a phylogenetic tree revealed that BSH-encoding lactobacilli primarily adopt the vertebrate-adapted lifestyle but not the environmental or plant-associated subsets. Phylogenetic analysis of the BSH sequences revealed two distinct clades, several conserved motifs, and the presence of six previously reported active-site residues. These data will guide future mechanistic studies of BSH activity and contribute to the development and selection of BSH-encoding strains with therapeutic potential. Bile acids play an integral role in shaping the gut microbiota and host physiology by regulating metabolic signaling, weight gain, and serum cholesterol and liver triglyceride levels. Given these important roles of bile acids, we investigated the presence of bile salt hydrolase (BSH) in genomes representing 170 different species, determined strain- and species-specific patterns of occurrences, and expanded on the diversity of the BSH repertoire in this genus. While our data showed that 28% of species encode BSH proteins, these species are associated mainly with vertebrate-adapted niches, demonstrating selective pressure on lactobacilli to evolve to adapt to specific environments. These new data will allow targeted selection of specific strains of lactobacilli and BSH proteins for future mechanistic studies to explore their therapeutic potential for treating metabolic disorders.
Topics: Adaptation, Biological; Amidohydrolases; Genetic Variation; Genotype; Lactobacillus; Penicillin Amidase; Phylogeny; Sequence Homology
PubMed: 29848760
DOI: 10.1128/mSphere.00140-18 -
BMJ (Clinical Research Ed.) Aug 1996To compare the effectiveness of penicillin V and amoxycillin with placebo in treatment of adult patients with acute sinusitis. (Clinical Trial)
Clinical Trial Randomized Controlled Trial
OBJECTIVES
To compare the effectiveness of penicillin V and amoxycillin with placebo in treatment of adult patients with acute sinusitis.
DESIGN
Randomised, double blind, placebo controlled trial.
SETTING
Norwegian general practice.
SUBJECTS
130 adult patients with a clinical diagnosis of acute sinusitis confirmed by computed tomography.
MAIN OUTCOME MEASURES
Subjective status after three and 10 days of treatment, difference in clinical severity score between day 0 and day 10 as evaluated by the general practitioner, difference in score from computed tomography on day 0 and day 10, and duration of sinusitis.
RESULTS
Amoxycillin and penicillin V led to significantly faster and better recovery than placebo. By day 10, 71 patients receiving antibiotic treatment- (86%) considered themselves to be recovered or much better compared with 25 (57%) receiving placebo. The mean (95% confidence interval) reductions in clinical severity scores by day 10 were 5.4 (5.0 to 5.8) for penicillin V, 5.5 (4.9 to 6.0 for amoxycillin, and 3.4 (2.8 to 4.0) for placebo. For the antibiotic groups combined the number of patients with the greatest degree of improvement on computed tomography (scale 0-16)-that is, score 5-16 on day 10-was 31/83 (37%) compared with 10/44 (23%) receiving placebo. The median duration of the sinusitis was nine days in the amoxycillin group, 11 days in the penicillin V group, and 17 days in the placebo group.
CONCLUSION
Penicillin V and amoxycillin are significantly more effective than placebo in the treatment of acute sinusitis.
Topics: Acute Disease; Adolescent; Adult; Aged; Amoxicillin; Bacterial Infections; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; Patient Satisfaction; Penicillin V; Penicillins; Placebos; Sinusitis; Treatment Outcome
PubMed: 8760738
DOI: 10.1136/bmj.313.7053.325 -
Antimicrobial Agents and Chemotherapy Apr 1996The efficacy and safety of a 3-day course of azithromycin oral suspension (10 mg/kg of body weight once daily) were compared with those of penicillin V (50,000 U/kg/day... (Clinical Trial)
Clinical Trial Comparative Study
The efficacy and safety of a 3-day course of azithromycin oral suspension (10 mg/kg of body weight once daily) were compared with those of penicillin V (50,000 U/kg/day in two divided doses) in children aged 3 to 12 years for the treatment of symptomatic pharyngitis caused by the group A beta-hemolytic streptococcus (GABHS). For the 154 evaluable patients, the original infecting strain of GABHS was eliminated at the end of follow-up (34 to 36 days after treatment started) from 67 (85.8%) of 78 penicillin-treated patients and 41 (53.9%) of 76 azithromycin-treated patients (P < 0.0001). Overall clinical success was achieved in 71 (91.0%) of 78 penicillin V-treated patients and 57 (75.0%) of 76 azithromycin-treated patients (P < 0.05). Potential drug-related adverse events were reported for 5.5 and 8.6% of the penicillin V- and azithromycin-treated patients, respectively (P = 0.6). In the present study, a once-daily (10 mg/kg), 3-day oral regimen of azithromycin was as safe as a 10-day course of penicillin but did not represent an effective alternative to penicillin for the treatment of GABHS pharyngitis, even for those children with azithromycin-susceptible strains.
Topics: Azithromycin; Child; Child, Preschool; Female; Humans; Male; Penicillin V; Pharyngitis; Streptococcus
PubMed: 8849215
DOI: 10.1128/AAC.40.4.1005 -
Photodiagnosis and Photodynamic Therapy Dec 2020This study used Electron Cryo-tomography (ECT) and fluorescent images to evaluate antimicrobial photodynamic therapy (aPDT) on the envelope architecture of a...
This study used Electron Cryo-tomography (ECT) and fluorescent images to evaluate antimicrobial photodynamic therapy (aPDT) on the envelope architecture of a Gram-negative bacteria and the effects of combined therapy of aPDT and antibiotics. Standard and clinical suspension of Escherichia coli were submitted to photodynamic treatment with methylene blue solution (100μM) and a 100 mW LED emitting at 660 nm with 3 and 18 J of energy. As a control group, a suspension of E. coli was submitted to penicillin V for 60 min at 30 °C, to compare the damage in cell wall structure. After treatment, ECT images were collected and E. coli biofilms were grown in glass-cover slides and stained with live/dead staining for fluorescence analysis before and after treatments. Bacteria were also submitted to disc diffusion and MIC tests with Ampicillin, Amoxicillin + Clavulanic acid, Clindamycin and Erythromycin. For in vivo experiment Galleria mellonella larvae were infected with E. coli and treated with antibiotics, aPDT or combined therapy. ECT images presented damage to cell walls and vesicles structures inside and outside the bacteria and fluorescent images showed dose dependent effect of aPDT. Antibiotic or aPDT alone did not improve the survival of caterpillars, but the combined therapy significantly increased survival curve. ECT and fluorescent images shows that aPDT seems to promote micro-damages to cell envelope and causes the production of membrane vesicles permeabilizing cell membranes. The results showed that pre-treating bacterial cells with a photosensitizer and light make them more susceptible to antibiotics and could be an alternative to local infection treatment by resistant bacteria.
Topics: Animals; Anti-Bacterial Agents; Anti-Infective Agents; Escherichia coli; Photochemotherapy; Photosensitizing Agents
PubMed: 32980553
DOI: 10.1016/j.pdpdt.2020.102029 -
Journal of Investigational Allergology... 2007Allergic reactions to beta-lactam antibiotics have been reported frequently and may occur because of sensitization to unique haptens or to determinants shared with other...
Allergic reactions to beta-lactam antibiotics have been reported frequently and may occur because of sensitization to unique haptens or to determinants shared with other drugs. A woman who received 1 tablet of amoxicillin-clavulanic acid developed wheals and flares although she had previously tolerated the same preparation well. Levels of specific immunoglobulin (Ig) E to penicillin V, penicillin G, amoxicillin, and ampicillin were undetectable. Skin tests to amoxicillin, penicillin major determinant and minor determinant mixture were negative. The patient tolerated oral challenge with 500 mg of amoxicillin but developed wheals and flares when challenged with amoxicillin-clavulanic acid 500/125 mg. A histamine release test was negative with amoxicillin but positive with the amoxicillin-clavulanic acid and clavulanic acid. A prick test to the combination was positive. Specific IgE to penicillin V later became positive while remaining negative to other beta-lactams. No inhibition was obtained using penicillin V against clavulanic acid and amoxicillin but was complete when penicillin V was used in the solid-phase and as the inhibitor. No cross-reactivity was proven between these sensitizations.
Topics: Adult; Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Drug Hypersensitivity; Female; Humans; Immunization; Immunoglobulin E; Penicillins; Skin Tests
PubMed: 17460951
DOI: No ID Found