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International Journal of Infectious... May 2017To compare the efficacy and safety of different pivmecillinam (PIV) regimes for uncomplicated lower urinary tract infections (UTIs). (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To compare the efficacy and safety of different pivmecillinam (PIV) regimes for uncomplicated lower urinary tract infections (UTIs).
METHODS
The MEDLINE, Embase, and Cochrane Library databases were searched. Randomized controlled clinical trials (RCTs) involving adults or children with symptoms suggestive of uncomplicated UTI and that compared different PIV regimes or PIV versus other antibiotics were included. Meta-analyses were conducted to obtain direct and indirect efficacy estimates. PIV regimes were categorized into high total dosage, moderate total dosage, and low total dosage. The risk of bias was evaluated using the Cochrane tool.
RESULTS
Twenty-four RCTs were identified. No difference in clinical cure was found for the high vs. moderate (short-term: risk ratio (RR) 1.01, p=0.813; long term: RR 1.09, p=0.174) or high vs. low dosage comparisons (mean difference 0, 95% confidence interval -0.44 to 0.45, p=1). For bacteriological cure, comparisons of high vs. moderate dosage (short term: RR 1.05, p=0.056; long term: RR 1.05, p=0.131) and high vs. low dosage (short term: RR 1.02, p=0.759; long term: RR 1.13, p=0.247) showed a trend in favor of the high dosage treatment. Results for relapse, re-infection, and failure were inconclusive and not statistically significant. Patients treated with high dosages were 40% (p=0.062) and 44% (p=0.293) more likely to report mild to moderate adverse events.
CONCLUSIONS
There is insufficient evidence to support the use of an optimal combination of dosage, frequency, and duration of PIV therapy for the treatment of uncomplicated lower UTI. Evidence is limited due to the high risk of bias, poor reporting, and heterogeneous study data.
Topics: Amdinocillin Pivoxil; Anti-Infective Agents, Urinary; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Urinary Tract Infections
PubMed: 28341436
DOI: 10.1016/j.ijid.2017.03.012 -
Microbiology Spectrum Jun 2023The lack of effective first-line antibiotic treatments against Neisseria gonorrhoeae, and the worldwide dissemination of resistant strains, are the main drivers of a...
The lack of effective first-line antibiotic treatments against Neisseria gonorrhoeae, and the worldwide dissemination of resistant strains, are the main drivers of a worsening global health crisis. β-lactam antibiotics have been the backbone of therapeutic armamentarium against gonococci. However, we are lacking critical insights to design rationally optimized therapies. In the present work, we generated the first PBP-binding data set on 18 currently available and clinically relevant β-lactams and 4 β-lactamase inhibitors in two N. gonorrhoeae ATCC type collection strains, 19424 and 49226 (PBP2 type XXII and A39T change in ). PBP binding (IC) was determined via the Bocillin FL binding assay in isolated membrane preparations. Three clusters of differential PBP ICs were identified and were mostly consistent across both strains, but with quantitative differences. Carbapenems were coselective for PBP2 and PBP3 (0.01 to 0.03 mg/L). Third- and fourth-generation cephalosporins cefixime, cefotaxime, ceftazidime, cefepime, and ceftriaxone showed the lowest IC values for PBP2 (0.01 mg/L), whereas cefoxitin, ceftaroline, and ceftolozane required higher concentrations (0.04 to >2 mg/L). Aztreonam was selective for PBP2 in both strains (0.03 to 0.07 mg/L); amdinocillin bound this PBP at higher concentrations (1.33 to 2.94 mg/L). Penicillins specifically targeted PBP2 in strain ATCC 19424 (0.02 to 0.19 mg/L) and showed limited inhibition in strain ATCC 49226 (0.01 to >2 mg/L). Preferential PBP2 binding was observed by β-lactam-based β-lactamase inhibitors sulbactam and tazobactam (1.07 to 6.02 mg/L); meanwhile, diazabicyclooctane inhibitors relebactam and avibactam were selective for PBP3 (1.27 to 5.40 mg/L). This data set will set the bar for future studies that will help the rational use and translational development of antibiotics against multidrug-resistant (MDR) N. gonorrhoeae. The manuscript represents the first N. gonorrhoeae PBP-binding data set for 22 chemically different drugs in two type strains with different genetic background. We have identified three clusters of drugs according to their PBP binding ICs and highlighted the binding differences across the two strains studied. With the currently available genomic information and the PBP-binding data, we have been able to correlate the target attainment differences and the mutations that affect the drug uptake with the MIC changes. The results of the current work will allow us to develop molecular tools of great practical use for the study and the design of new rationally designed therapies capable of combating the growing MDR gonococci threat.
Topics: Humans; beta-Lactams; beta-Lactamase Inhibitors; Penicillin-Binding Proteins; Neisseria gonorrhoeae; Anti-Bacterial Agents; Penicillins; Ceftazidime; Gonorrhea; Microbial Sensitivity Tests; Bacterial Proteins
PubMed: 37093051
DOI: 10.1128/spectrum.00692-23 -
Trials Sep 2023Oral treatment alternatives for febrile urinary tract infections are limited in the era of increasing antimicrobial resistance. We aim to evaluate if the combination of...
BACKGROUND
Oral treatment alternatives for febrile urinary tract infections are limited in the era of increasing antimicrobial resistance. We aim to evaluate if the combination of pivmecillinam and amoxicillin/clavulanic acid is non-inferior to current alternatives for step-down therapy in adult patients with febrile urinary tract infection.
METHODS
We plan to perform an investigator-initiated non-inferiority trial. Adult hospitalised patients treated with 1-5 days of intravenous antibiotics for acute febrile urinary tract infection caused by extended spectrum beta-lactamase (ESBL) producing Enterobacterales will be randomised 1:1 to either control (7-10 days of either oral ciprofloxacin 500 mg twice daily or oral trimethoprim-sulfamethoxazole 800 mg/160 mg twice daily or intravenous ertapenem 1 g once daily, depending on sex, drug allergy, glomerular filtration rate and susceptibility testing) or intervention (10 days of pivmecillinam 400 mg three times daily and amoxicillin/clavulanic acid 500/125 mg three times daily). The primary outcome will be clinical cure 10 days (+/- 2 days) after antibiotic treatment completion. Clinical cure is defined as being alive with absence of fever and return to non-infected baseline of urinary tract symptoms without additional antibiotic treatment or re-hospitalisation (for urinary tract infection) based on a centralised allocation-blinded structured telephone interview. We plan to recruit 330 patients to achieve 90% power based on a sample size simulation analysis using a two-group comparison, one-sided alpha of 2.5%, an absolute non-inferiority margin of 10% and expecting 93% clinical cure rate and 10% loss to follow-up. The primary endpoint will be analysed using generalised estimated equations and reported as risk difference for both intention-to-treat and per protocol populations. Patients are planned to be recruited from at least 10 centres in Sweden from 2023 to 2026.
DISCUSSION
If the combination of pivmecillinam and amoxicillin/clavulanic acid is found to be non-inferior to the control drugs there are potential benefits in terms of tolerability, frequency of interactions, outpatient treatment, side effects, nosocomial infections and drive for further antimicrobial resistance compared to existing drugs.
TRIAL REGISTRATION
NCT05224401. Registered on February 4, 2022.
Topics: Adult; Humans; Amoxicillin-Potassium Clavulanate Combination; Amdinocillin Pivoxil; Anti-Bacterial Agents; Urinary Tract Infections; Clavulanic Acid; Fever
PubMed: 37660037
DOI: 10.1186/s13063-023-07542-3 -
Antimicrobial Agents and Chemotherapy Feb 2022QPX7728 is a cyclic boronate ultrabroad-spectrum beta-lactamase inhibitor, with potent activity against both serine beta-lactamases and metallo-beta-lactamases. QPX7728...
The Ultrabroad-Spectrum Beta-Lactamase Inhibitor QPX7728 Restores the Potency of Multiple Oral Beta-Lactam Antibiotics against Beta-Lactamase-Producing Strains of Resistant .
QPX7728 is a cyclic boronate ultrabroad-spectrum beta-lactamase inhibitor, with potent activity against both serine beta-lactamases and metallo-beta-lactamases. QPX7728 can be delivered systemically by the intravenous (i.v.) or oral route of administration. Oral beta-lactam antibiotics alone or in combination with QPX7728 were evaluated for (i) sensitivity to hydrolysis by various common beta-lactamases and inhibition of hydrolysis by QPX7728, (ii) the impact of non-beta-lactamase-mediated resistance mechanisms on potency of beta-lactams, and (iii) activity against a panel of clinical strains producing diverse beta-lactamases. The carbapenem tebipenem had stability for many serine beta-lactamases from all molecular classes, followed by the cephalosporin ceftibuten. Addition of QPX7728 to tebipenem, ceftibuten, and amdinocillin completely reversed beta-lactamase-mediated resistance in cloned beta-lactamases from serine enzyme and metalloenzyme classes; the degree of potentiation of other beta-lactams varied according to the beta-lactamase produced. Tebipenem, ceftibuten, and cefixime had the lowest MICs against laboratory strains with various combinations of beta-lactamases and the intrinsic drug resistance mechanisms of porin and efflux mutations. There was a high degree of correlation between potency of various combinations against cloned beta-lactamases and efflux/porin mutants and the activity against clinical isolates, showing the importance of inhibition of beta-lactamase along with minimal impact of general intrinsic resistance mechanisms affecting the beta-lactam. Tebipenem and ceftibuten appeared to be the best beta-lactam antibiotics when combined with QPX7728 for activity against that produce serine beta-lactamases or metallo-beta-lactamases.
Topics: Anti-Bacterial Agents; Borinic Acids; Carboxylic Acids; Microbial Sensitivity Tests; beta-Lactamase Inhibitors; beta-Lactamases; beta-Lactams
PubMed: 34902261
DOI: 10.1128/AAC.02168-21 -
Antimicrobial Agents and Chemotherapy Dec 1986Compared with cefotaxime, ceftazidime, moxalactam, and aztreonam, ceftriaxone produced the best lytic and bactericidal effects when each was added at about 10 times the...
Involvement of penicillin-binding protein 2 with other penicillin-binding proteins in lysis of Escherichia coli by some beta-lactam antibiotics alone and in synergistic lytic effect of amdinocillin (mecillinam).
Compared with cefotaxime, ceftazidime, moxalactam, and aztreonam, ceftriaxone produced the best lytic and bactericidal effects when each was added at about 10 times the MIC to Escherichia coli W7. When each of these antibiotics was added at its MIC, only bacteriostasis occurred, but the simultaneous addition of amdinocillin (mecillinam) was synergistic in causing rapid lysis and bactericidal effects. Induction of lysis of two E. coli mutants containing either a thermosensitive penicillin-binding protein (PBP) 2 or 3 by relatively PBP 3-specific (aztreonam) and PBP 2-specific (amdinocillin) antibiotics indicated that inhibition of only PBPs 2 and 3 can cause lysis. Examination of the interactions of cefotaxime, aztreonam, and cefsulodin, with or without amdinocillin, with their targets suggested that other combinations of PBPs could be involved in the onset of lysis. However, inhibition of both PBPs 2 and 3 may explain the better lysis-inducing activity of ceftriaxone (which binds well to both of these PBPs), as well as the synergistic effect of amdinocillin when added together with low concentrations of other beta-lactam antibiotics that interact with PBP 3.
Topics: Acyltransferases; Amdinocillin; Anti-Bacterial Agents; Bacterial Proteins; Bacteriolysis; Carrier Proteins; Drug Synergism; Escherichia coli; Hexosyltransferases; Microscopy, Electron, Scanning; Multienzyme Complexes; Muramoylpentapeptide Carboxypeptidase; Penicillin-Binding Proteins; Peptidyl Transferases; Temperature
PubMed: 3545069
DOI: 10.1128/AAC.30.6.906 -
Molecular Cell May 2021The multi-subunit bacterial RNA polymerase (RNAP) and its associated regulators carry out transcription and integrate myriad regulatory signals. Numerous studies have...
The multi-subunit bacterial RNA polymerase (RNAP) and its associated regulators carry out transcription and integrate myriad regulatory signals. Numerous studies have interrogated RNAP mechanism, and RNAP mutations drive Escherichia coli adaptation to many health- and industry-relevant environments, yet a paucity of systematic analyses hampers our understanding of the fitness trade-offs from altering RNAP function. Here, we conduct a chemical-genetic analysis of a library of RNAP mutants. We discover phenotypes for non-essential insertions, show that clustering mutant phenotypes increases their predictive power for drawing functional inferences, and demonstrate that some RNA polymerase mutants both decrease average cell length and prevent killing by cell-wall targeting antibiotics. Our findings demonstrate that RNAP chemical-genetic interactions provide a general platform for interrogating structure-function relationships in vivo and for identifying physiological trade-offs of mutations, including those relevant for disease and biotechnology. This strategy should have broad utility for illuminating the role of other important protein complexes.
Topics: Amdinocillin; Bacterial Proteins; Cell Death; Chromosomes, Bacterial; Cytoprotection; Cytoskeletal Proteins; DNA-Directed RNA Polymerases; Escherichia coli; Gene Expression Regulation, Bacterial; Mutagenesis, Insertional; Mutation; Peptides; Phenotype; Structure-Activity Relationship; Transcription, Genetic; Uridine Diphosphate Glucose
PubMed: 34019789
DOI: 10.1016/j.molcel.2021.04.027 -
Frontiers in Microbiology 2020: To investigate the susceptibility of carbapenemase-producing Enterobacterales (CPE) to mecillinam based on the recently updated European Committee on Antimicrobial...
: To investigate the susceptibility of carbapenemase-producing Enterobacterales (CPE) to mecillinam based on the recently updated European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints for uncomplicated Urinary Tract Infection (uUTI). : The challenge collection consisted of 105 molecularly characterized Enterobacterales [ spp. ( = 49), ( = 30), ( = 13), ( = 9), ( = 3), and ( = 1)]. Isolates produced OXA-48 ( = 18), OXA-48-like ( = 18), VIM ( = 22), NDM ( = 22), KPC ( = 12), IMI ( = 9), IMP ( = 6), GES ( = 1), OXA-58 ( = 2) or combinations thereof ( = 5). MICs of carbapenems were determined by agar gradient diffusion (AGD). MICs of mecillinam were assessed by agar dilution (reference method) and compared to disk diffusion (DD) and AGD. : Overall 23/105 CPE (21.9%) were susceptible to mecillinam. Susceptibility was observed in ( = 12), ( = 7), and ( = 4) producing IMI, OXA-48, OXA-48-like, and NDM-1 carbapenemases. MIC for mecillinam in all isolates was 128 mg/L while MIC for meropenem was 8 mg/L. Lower MICs for mecillinam were found in IMI (MIC 8 mg/L) and OXA-48-like (MIC 16 mg/L) producers. The comparison of the different susceptibility methods showed very major errors of 12.2% with AGD and 8.5% with disk diffusion when compared to the reference method. : Mecillinam susceptibility was restricted to isolates producing IMI-, OXA-48-like, and NDM-1 carbapenemases and was documented despite high carbapenem MICs in some isolates. Mecillinam could be a promising oral antimicrobial in uUTI caused by and isolates carrying IMI- and OXA-48-like carbapenemases; however, susceptibility testing by AGD and disk diffusion remains problematic.
PubMed: 33510739
DOI: 10.3389/fmicb.2020.627267 -
Journal of Clinical Microbiology Sep 2018A rectal culture-guided antimicrobial prophylaxis strategy may prevent infections after transrectal ultrasound-guided prostate biopsy (TRUSP). The use of selective...
A rectal culture-guided antimicrobial prophylaxis strategy may prevent infections after transrectal ultrasound-guided prostate biopsy (TRUSP). The use of selective culture media could assist the choice of appropriate antibiotic prophylaxis. The objective of our study was to evaluate the performance of four selective media used for guidance of oral antibiotic prophylaxis in TRUSP. In this prospective validation study, we used MacConkey media with vancomycin plus one of the following antibiotics: ciprofloxacin (McC3+CIP/V), trimethoprim (McC3+TMP/V), fosfomycin (McC3+FOF/V), and amdinocillin-amoxicillin-clavulanic acid (McC3+MEC/V). First, clinical strains of Gram-negative bacilli (GNB) ( = 33) were evaluated for growth on the selective media. Thereafter, rectal swabs ( = 97) were randomly collected from residual material of fresh stool samples and plated on a growth control and the four selective media. Levels of recovery of GNB on the growth control and selective media were compared, and the MICs of the antibiotics used in this study were determined. The sensitivity and specificity of the four selective media amounted, respectively, to 90.0% (55.5 to 99.8%) and 98.7% (93.1 to 100.0%) for McC3+CIP/V, 95.7% (85.2 to 99.5%) and 100.0% (91.6 to 100.0%) for McC3+TMP/V, 95.5% (84.5 to 99.4%) and 97.8% (88.2 to 99.9%) for McC3+FOF/V, and 100.0% (76.8 to 100.0%) and 97.6% (87.4 to 99.9%) for McC3+MEC/V. In conclusion, the four selective media were sufficiently sensitive and specific for the identification of rectal GNB resistant to ciprofloxacin, trimethoprim, fosfomycin, or amdinocillin-amoxicillin-clavulanic acid. These media can have added value in streamlining the optimal culture based antibiotic prophylaxis in TRUSP in a non-labor-intensive manner.
Topics: Anti-Bacterial Agents; Antibiotic Prophylaxis; Clinical Decision-Making; Culture Media; Drug Resistance, Bacterial; Feces; Gram-Negative Bacteria; Humans; Image-Guided Biopsy; Male; Microbial Sensitivity Tests; Postoperative Complications; Prospective Studies; Prostate; Rectum; Sensitivity and Specificity
PubMed: 29899004
DOI: 10.1128/JCM.00253-18 -
International Journal of Antimicrobial... May 2022Urinary tract infections (UTIs) are prevalent worldwide, particularly among women. Their incidence increases with age, and treatment is increasingly challenging owing to...
Urinary tract infections (UTIs) are prevalent worldwide, particularly among women. Their incidence increases with age, and treatment is increasingly challenging owing to antibiotic resistance and the lack of new agents. We investigated the susceptibility of current urinary isolates to fosfomycin and other antibiotics across Europe. This cross-sectional study collected consecutive urinary isolates from non-hospitalised women at 20 centres in Belgium, the UK, Italy, Spain and Russia. Bacteria were tested by disk diffusion with relevant antibiotics. As a quality control, a central laboratory re-tested, by agar dilution, (i) isolates found resistant to fosfomycin and (ii) every tenth isolate; all non-Russian sites were included. A total of 2848 isolates were analysed, principally Escherichia coli (2064; 72.5%), Klebsiella spp. (275; 9.7%) and Proteus spp. (103; 3.6%). For E. coli, agents active against >90% of isolates were nitrofurantoin (98.5%), fosfomycin (96.4%) and mecillinam (91.8%). Fosfomycin and nitrofurantoin remained active against >90% of cephalosporin-resistant E. coli. Among 143 E. coli recorded as susceptible locally by disk tests, 138 (96.5%) were confirmed susceptible by minimum inhibitory concentration (MIC) tests, however resistance was only confirmed in 29/58 (50.0%) of those reported resistant by local disk tests. Escherichia coli was found to be the most common uropathogen isolated and was highly susceptible to fosfomycin, nitrofurantoin and mecillinam, all used effectively for more than 30 years. Guidelines advocating fosfomycin for uncomplicated UTIs in women remain microbiologically valid.
Topics: Amdinocillin; Anti-Bacterial Agents; Cross-Sectional Studies; Escherichia coli; Escherichia coli Infections; Female; Fosfomycin; Humans; Male; Microbial Sensitivity Tests; Nitrofurantoin; Urinary Tract Infections
PubMed: 35307561
DOI: 10.1016/j.ijantimicag.2022.106574 -
Antimicrobial Agents and Chemotherapy Nov 1988Enterobacter cloacae infections have been shown clinically to respond less reliably to monotherapy with broad-spectrum cephalosporins than was initially expected....
Enterobacter cloacae infections have been shown clinically to respond less reliably to monotherapy with broad-spectrum cephalosporins than was initially expected. Selection of populations producing high levels of beta-lactamase has been shown to be the most frequent reason for treatment failure, and the use of these agents with another active antibiotic is recommended. In this study, E. cloacae strains from clinical specimens susceptible to ceftazidime and amdinocillin by broth dilution and disk tests were examined. In the presence of ceftazidime at 10 micrograms/ml, in vitro selection of resistant organisms was demonstrated for 3 of 11 strains. Selection was prevented when amdinocillin was added in combination. A more rapid killing was also demonstrated with this combination. At inocula of 10(8) CFU/ml, ceftazidime-resistant populations were isolated from 6 of 11 strains in vitro, and the emergence of this resistance was prevented by amdinocillin. The enhanced killing effect noted for amdinocillin with ceftazidime may have resulted in part from complementary activity of the antibiotics on penicillin-binding proteins. The ceftazidime-amdinocillin combination offers an interesting prospect for the therapy of infections caused by E. cloacae strains which are initially susceptible to both antibiotics.
Topics: Amdinocillin; Ceftazidime; Drug Combinations; Drug Resistance, Microbial; Enterobacter; Enterobacteriaceae; Microbial Sensitivity Tests
PubMed: 3075433
DOI: 10.1128/AAC.32.11.1632