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Lakartidningen Aug 2020
Topics: Amdinocillin Pivoxil; Humans; Pyelonephritis
PubMed: 32852775
DOI: No ID Found -
Antimicrobial Agents and Chemotherapy Mar 2015Amdinocillin (mecillinam) is a β-lactam antibiotic that is used mainly for the treatment of uncomplicated urinary tract infections. The objectives of this study were to...
Amdinocillin (mecillinam) is a β-lactam antibiotic that is used mainly for the treatment of uncomplicated urinary tract infections. The objectives of this study were to identify mutations that confer amdinocillin resistance on laboratory-isolated mutants and clinical isolates of Escherichia coli and to determine why amdinocillin resistance remains rare clinically even though resistance is easily selected in the laboratory. Under laboratory selection, frequencies of mutation to amdinocillin resistance varied from 8 × 10(-8) to 2 × 10(-5) per cell, depending on the concentration of amdinocillin used during selection. Several genes have been demonstrated to give amdinocillin resistance, but here eight novel genes previously unknown to be involved in amdinocillin resistance were identified. These genes encode functions involved in the respiratory chain, the ribosome, cysteine biosynthesis, tRNA synthesis, and pyrophosphate metabolism. The clinical isolates exhibited significantly greater fitness than the laboratory-isolated mutants and a different mutation spectrum. The cysB gene was mutated (inactivated) in all of the clinical isolates, in contrast to the laboratory-isolated mutants, where mainly other types of more costly mutations were found. Our results suggest that the frequency of mutation to amdinocillin resistance is high because of the large mutational target (at least 38 genes). However, the majority of these resistant mutants have a low growth rate, reducing the probability that they are stably maintained in the bladder. Inactivation of the cysB gene and a resulting loss of cysteine biosynthesis are the major mechanism of amdinocillin resistance in clinical isolates of E. coli.
Topics: Amdinocillin; Bacterial Proteins; Drug Resistance, Bacterial; Escherichia coli; Laboratories; Mutation
PubMed: 25583718
DOI: 10.1128/AAC.04819-14 -
The Journal of Antimicrobial... Sep 2022Despite the fact that carbapenem-resistant Enterobacterales (CRE) mostly cause urinary tract infections (UTIs), only few studies have focused on the efficacity of...
BACKGROUND
Despite the fact that carbapenem-resistant Enterobacterales (CRE) mostly cause urinary tract infections (UTIs), only few studies have focused on the efficacity of mecillinam against these CRE.
OBJECTIVES
To evaluate the mecillinam susceptibility of a huge collection of CRE, including carbapenemase-producing Enterobacterales (CPE) and non-CPE (ESBL and AmpC producers with decreased permeability of the outer membrane).
METHODS
A total of 8310 non-duplicate clinical CRE, including 4042 OXA-48-like producers, 1094 NDM producers, 411 VIM producers, 174 KPC producers, 42 IMI producers, 153 multiple-carbapenemase producers and 45 isolates producing other types of carbapenemases (such as IMP-like enzymes or GES-5), were included in the study. WGS was performed on all CPE using Illumina technology. Categorization of susceptibility to mecillinam was performed using disc diffusion (mecillinam discs at 10 μg; I2A, France) according to EUCAST recommendations. The results were interpreted according to EUCAST guidelines (S ≥15 mm).
RESULTS
Significantly higher susceptibility rates were observed for carbapenem-resistant Proteus spp. (85%) and carbapenem-resistant Escherichia coli (84%), which are the two most common species responsible for UTIs, than for Klebsiella pneumoniae (67%), Enterobacter cloacae complex (75%), Citrobacter spp. (65%), Serratia spp. (34%) and Morganella morganii (12%). Susceptibility rates were 84%, 71% and 91% for OXA-48-like, NDM and IMI producers and 70% for non-CPE CRE. Mecillinam was less active against VIM and KPC producers (14% and 0%, respectively).
CONCLUSIONS
Mecillinam might be an alternative for the treatment of infections due to CRE, particularly UTIs, except for VIM and KPC producers and for M. morganii and Serratia spp species.
Topics: Humans; Amdinocillin; Bacterial Proteins; beta-Lactamases; Carbapenems; Enterobacteriaceae Infections; Escherichia coli; Microbial Sensitivity Tests; Urinary Tract Infections
PubMed: 35815675
DOI: 10.1093/jac/dkac226 -
International Journal of Epidemiology Apr 2010Ciprofloxacin, ceftriaxone and pivmecillinam are the antibiotics currently recommended by the World Health Organization (WHO) for the treatment of dysentery in children;... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Ciprofloxacin, ceftriaxone and pivmecillinam are the antibiotics currently recommended by the World Health Organization (WHO) for the treatment of dysentery in children; yet there have been no reviews of the clinical effectiveness of these antibiotics in recent years.
METHODS
We reviewed all literature reporting the effect of ciprofloxacin, ceftriaxone and pivmecillinam for the treatment of dysentery in children in the developing countries. We used a standardized abstraction and grading format and performed meta-analyses to determine the effect of treatment with these antibiotics on rates of treatment failure, bacteriological failure and bacteriological relapse. The CHERG Standard Rules were applied to determine the final effect of treatment with these antibiotics on diarrhoea mortality.
RESULTS
Eight papers were selected for abstraction. Treatment with ciprofloxacin, ceftriaxone or pivmecillinam resulted in a cure rate of >99% while assessing clinical failure, bacteriological failure and bacteriological relapse.
CONCLUSIONS
The antibiotics recommended by the WHO--ciprofloxacin, ceftriaxone and pivmecillinam--are effective in reducing the clinical and bacteriological signs and symptoms of dysentery and thus can be expected to decrease diarrhoea mortality attributable to dysentery.
Topics: Amdinocillin Pivoxil; Anti-Bacterial Agents; Ceftriaxone; Child, Preschool; Ciprofloxacin; Dysentery; Dysentery, Bacillary; Female; Humans; Infant; Male; Randomized Controlled Trials as Topic; Salmonella Infections; Shigella dysenteriae; Treatment Outcome
PubMed: 20348130
DOI: 10.1093/ije/dyq024 -
PLoS Biology Sep 2020Antibiotic combination therapies are important for the efficient treatment of many types of infections, including those caused by antibiotic-resistant pathogens....
Antibiotic combination therapies are important for the efficient treatment of many types of infections, including those caused by antibiotic-resistant pathogens. Combination treatment strategies are typically used under the assumption that synergies are conserved across species and strains, even though recent results show that the combined treatment effect is determined by specific drug-strain interactions that can vary extensively and unpredictably, both between and within bacterial species. To address this problem, we present a new method in which antibiotic synergy is rapidly quantified on a case-by-case basis, allowing for improved combination therapy. The novel CombiANT methodology consists of a 3D-printed agar plate insert that produces defined diffusion landscapes of 3 antibiotics, permitting synergy quantification between all 3 antibiotic pairs with a single test. Automated image analysis yields fractional inhibitory concentration indices (FICis) with high accuracy and precision. A technical validation with 3 major pathogens, Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus, showed equivalent performance to checkerboard methodology, with the advantage of strongly reduced assay complexity and costs for CombiANT. A synergy screening of 10 antibiotic combinations for 12 E. coli urinary tract infection (UTI) clinical isolates illustrates the need for refined combination treatment strategies. For example, combinations of trimethoprim (TMP) + nitrofurantoin (NIT) and TMP + mecillinam (MEC) showed synergy, but only for certain individual isolates, whereas MEC + NIT combinations showed antagonistic interactions across all tested strains. These data suggest that the CombiANT methodology could allow personalized clinical synergy testing and large-scale screening. We anticipate that CombiANT will greatly facilitate clinical and basic research of antibiotic synergy.
Topics: Algorithms; Amdinocillin; Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Escherichia coli; Escherichia coli Infections; Humans; Microbial Sensitivity Tests; Nitrofurantoin; Pseudomonas Infections; Pseudomonas aeruginosa; Reproducibility of Results; Staphylococcal Infections; Staphylococcus aureus; Trimethoprim; Urinary Tract Infections
PubMed: 32941420
DOI: 10.1371/journal.pbio.3000856 -
Infection and Drug Resistance 2018The pharmacokinetic properties of mecillinam (MEC) for urinary tract infections are excellent, and the resistance rate in Enterobacteriaceae is low compared to other... (Review)
Review
PURPOSE
The pharmacokinetic properties of mecillinam (MEC) for urinary tract infections are excellent, and the resistance rate in Enterobacteriaceae is low compared to other recommended antibiotics. The oral prodrug pivmecillinam (P-MEC) has been used successfully as first choice for cystitis in the Nordic countries for many years. Norwegian and Danish guidelines also recommend P-MEC for acute uncomplicated pyelonephritis (AUP) and intravenous (IV) MEC for suspected urosepsis (only in Denmark). Here, we wish to present an updated investigation on the clinical data behind these recommendations together with sparse but more current clinical data.
METHODS
Prospective clinical trials evaluating MEC as monotherapy or in polytherapy with one other beta-lactam (mostly ampicillin [AMP]) for pyelonephritis or bacteremia were reviewed. Outcomes of primary interest were clinical and bacteriological success and relapse, respectively. Search databases used were PubMed, Cochrane Library, and Embase.
RESULTS
Twelve clinical studies (1979-2015) were included in this integrated literature review. Clinical success was seen in 38/51 (75%) patients treated with MEC as monotherapy and in 152/164 (93%) patients treated with MEC and one other beta-lactam. Bacteriological success was seen in 35/47 (74%) and 117/167 (70%) patients treated with MEC alone and with one other beta-lactam, respectively. In complicated infections, bacteriological success was much lower. Clinical relapse rate was not well described. Several uropathogenic bacteremia cases were treated successfully with MEC alone (ie, 10/15 [67%] and 13/15 [87%] for clinical and bacteriological success, respectively) or with one other beta-lactam (ie, 57/65 [88%] and 53/63 [84%] for clinical and bacteriological success, respectively). However, data on bacteremia are very sparse. Adverse reactions were few and mild (73/406 [18%]) and primarily seen when AMP was co-administered (69/73 [95%]). No serious adverse reactions were reported.
CONCLUSION
IV MEC or oral P-MEC for 14 days may be suitable for the treatment of AUP and pediatric pyelonephritis. Randomized controlled trials using a single standardized dose of P-MEC compared to other current recommendations are warranted. Similarly, more evidence is required before MEC should be recommended for bacteremia or sepsis due to Enterobacteriaceae.
PubMed: 29872326
DOI: 10.2147/IDR.S163280 -
Journal of Bacteriology Jan 2018A hallmark of bacterial biofilms is the production of an xtraellular atrix (ECM) that encases and protects the community from environmental stressors. Biofilm formation...
A hallmark of bacterial biofilms is the production of an xtraellular atrix (ECM) that encases and protects the community from environmental stressors. Biofilm formation is an integral portion of the roathogenic (UPEC) life cycle. Approximately 2% of UPEC isolates are cysteine auxotrophs. Here, we investigated how cysteine homeostasis impacted UPEC UTI89 strain biofilm formation and, specifically, the production of the ECM components curli and cellulose. Cysteine auxotrophs produced less cellulose and slightly more curli compared to wild-type (WT) strains, and cysteine auxotrophs formed smooth, nonrugose colonies. Cellulose production was restored in cysteine auxotrophs when YfiR was inactivated. YfiR is a redox-sensitive regulator of the diguanylate cyclase, YfiN. The production of curli, a temperature-regulated appendage, was independent of temperature in UTI89 cysteine auxotrophs. In a screen of UPEC isolates, we found that ∼60% of UPEC cysteine auxotrophs produced curli at 37°C, but only ∼2% of cysteine prototrophic UPEC isolates produced curli at 37°C. Interestingly, sublethal concentrations of amdinocillin and trimethoprim-sulfamethoxazole inhibited curli production, whereas strains auxotrophic for cysteine continued to produce curli even in the presence of amdinocillin and trimethoprim-sulfamethoxazole. The dysregulation of ECM components and resistance to amdinocillin in cysteine auxotrophs may be linked to hyperoxidation, since the addition of exogenous cysteine or glutathione restored WT biofilm phenotypes to mutants unable to produce cysteine and glutathione. Uropathogenic (UPEC) bacteria are the predominant causative agent of urinary tract infections (UTIs). UTIs account for billions of dollars of financial burden annually to the health care industry in the United States. Biofilms are an important aspect of the UPEC pathogenesis cascade and for the establishment of chronic infections. Approximately 2% of UPEC isolates from UTIs are cysteine auxotrophs, yet there is relatively little known about the biofilm formation of UPEC cysteine auxotrophs. Here we show that cysteine auxotrophs have dysregulated biofilm components due to a change in the redox state of the periplasm. Additionally, we show the relationship between cysteine auxotrophs, biofilms, and antibiotics frequently used to treat UTIs.
Topics: Biofilms; Cysteine; Escherichia coli Proteins; Extracellular Matrix; Gene Expression Regulation, Bacterial; Oxidation-Reduction; Periplasm; Sulfhydryl Compounds; Uropathogenic Escherichia coli
PubMed: 29038256
DOI: 10.1128/JB.00389-17 -
British Journal of Clinical Pharmacology Jun 19771 The plasma concentration/time curves of ampicillin and mecillinam in normal subjects were measured after oral administration of ampicillin (500 mg) and pivmecillinam...
1 The plasma concentration/time curves of ampicillin and mecillinam in normal subjects were measured after oral administration of ampicillin (500 mg) and pivmecillinam (400 and 600 mg). 2 Similar plasma concentration/time curves of ampicillin and mecillinam in the starved normal subjects followed oral administration of ampicillin (500 mg) and pivmecillinam (600 mg). 3 The plasma concentration/time curve of mecillinam was measured in the same normal subjects after oral administration of pivmecillinam (400 mg) with a reproducible standardized Lundh test meal. 4 There was no statistically significant difference in the plasma concentration/time curve of mecillinam after pivmecillinam/400 mg) and the meal compared with the plasma concentration/time curve after oral pivmecillinam (400 mg) was given to the same subjects when starved. After administration of pivmecillinam (400 mg) with meal, Tasc was significantly delayed beyond the value obtained when the subjects were starved. 5 The pharmacokinetics of pivmecillinam in coeliac disease are normal. This finding contrasts with previous studies on the pharmacokinetics of another pivaloyloxymethylpenicillin ester, pivampicillin, in this condition.
Topics: Adolescent; Adult; Amdinocillin Pivoxil; Ampicillin; Biological Assay; Celiac Disease; Escherichia coli; Food; Humans; Intestinal Absorption; Kinetics; Middle Aged; Penicillanic Acid; Sarcina; Starvation
PubMed: 197981
DOI: 10.1111/j.1365-2125.1977.tb00711.x -
Euro Surveillance : Bulletin Europeen... May 2023IntroductionEmpirical therapy for the treatment of urinary tract infections should be tailored to the current distribution and susceptibility of potential pathogens to...
IntroductionEmpirical therapy for the treatment of urinary tract infections should be tailored to the current distribution and susceptibility of potential pathogens to ensure optimal treatment.AimWe aimed to provide an up-to-date overview of the epidemiology and susceptibility of Enterobacterales isolated from urine in Germany.MethodsWe retrospectively analysed antimicrobial susceptibility data from 201,152 urine specimens collected between January 2016 and June 2021 from in- and outpatients. Multiple logistic regression analysis was used to evaluate the association between year of investigation and antibiotic resistance, adjusted for age, sex and species subgroup. Subgroup analyses were performed for midstream urine samples obtained from (i) female outpatients aged 15 to 50 years, (ii) female outpatients older than 50 years and (iii) male outpatients.ResultsResistance rates of less than 20% were observed for nitroxoline (3.9%), fosfomycin (4.6%), nitrofurantoin (11.7%), cefuroxime (13.5%) and ciprofloxacin (14.2%). Resistance to trimethoprim/sulfamethoxazole (SXT) (20.1%), amoxicillin-clavulanic acid (20.5%), trimethoprim (24.2%), pivmecillinam (29.9%) and ampicillin (53.7%) was considerably higher. In the subgroup of outpatient women aged 15-50 years, resistance rates were generally lower. Resistance rates of all antibiotics decreased from 2016 to 2021. Multiple logistic regression revealed the lowest adjusted odds ratio (ORadj) of 0.838 (95% confidence interval (CI): 0.819-0.858; p < 0.001) for pivmecillinam and the highest ORadj of 0.989 (95% CI: 0.972-1.007; p = 0.226) for nitrofurantoin.ConclusionsResistance has generally decreased over the past years, independent of sex, age and causative pathogen. Our data provide an important basis for empirical antibiotic recommendations in various settings and patient collectives.
Topics: Female; Male; Humans; Anti-Bacterial Agents; Nitrofurantoin; Amdinocillin Pivoxil; Retrospective Studies; Escherichia coli; Drug Resistance, Bacterial; Urinary Tract Infections; Trimethoprim, Sulfamethoxazole Drug Combination; Germany; Microbial Sensitivity Tests; Escherichia coli Infections
PubMed: 37166759
DOI: 10.2807/1560-7917.ES.2023.28.19.2200568