Carbapenems are now being explored for treatment of multidrug-resistant tuberculosis (MDR-TB), especially in conjunction with clavulanate. Clinical use is constrained by the need for multiple ...parenteral doses per day and the lack of knowledge of the optimal dose for sterilizing effect. Our objective was to identify the ertapenem exposure associated with optimal sterilizing effect and then design a once-a-day dose for clinical use. We utilized the hollow-fiber system model of tuberculosis in a 28-day exposure-response study of 8 different ertapenem doses in combination with clavulanate. The systems were sampled at predetermined time points to verify the concentration-time profile and identify the total bacterial burden. Inhibitory sigmoid maximum-effect (
) modeling was used to identify the relationship between total bacterial burden and the drug exposure and to identify optimal exposures. Contrary to the literature, ertapenem-clavulanate combination demonstrated good microbial kill and sterilizing effect. In a dose fractionation hollow-fiber study, efficacy was linked to percentage of the 24-h dosing interval of ertapenem concentration persisting above MIC (%
). We performed 10,000 MDR-TB patient computer-aided clinical trial simulations, based on Monte Carlo methods, to identify the doses and schedule that would achieve or exceed a %
of ≥40%. We identified an intravenous dosage of 2 g once per day as achieving the target in 96% of patients. An ertapenem susceptibility breakpoint MIC of 2 mg/liter was identified for that dose. An ertapenem dosage of 2 g once daily is the most suitable to be tested in a phase II study of sterilizing effect in MDR-TB patients.
Five commercially available amoxicillin-clavulanate (AMC) ratio formulations contribute to ratio selection variability with efficacy and toxicity implications. The objective of this survey was to ...determine AMC formulation use patterns across the United States.
A multicenter practitioner survey was distributed to multiple listservs (American College of Clinical Pharmacy pediatrics, infectious diseases, ambulatory care, pharmacy administration; American Society of Health-System Pharmacists; Pediatric Pharmacy Association members), and selected pediatric Vizient members in June 2019. Responses were screened for multiples within institutions. Repeated organization responses were identified (n = 37) and excluded if the duplicate matched another response from the same organization exactly (n = 0).
One hundred ninety independent responses were received. Nearly 62% of respondents represented a children's hospital within an acute care hospital; remainder being from stand-alone children's hospitals. Around 55% of respondents indicated prescribers were responsible for choosing the patient-specific formulation for inpatients. Nearly 70% of respondents indicated multiple formulations were available due to clinical need (efficacy, toxicity, measurable volume), whereas over 40% responded that the number of liquid formulations were limited to decrease the potential for error. Variability was demonstrated among institutions using ≥ 2 different formulations for acute otitis media (AOM), sinusitis, lower respiratory tract infection, skin and soft tissue infection, and urinary tract infection (33.6%, 37.3%, 41.5%, 35.8%, and 35.8%, respectively). The 14:1 formulation was the most common, but not exclusive, for AOM, sinusitis, and lower respiratory tract infections with 2.1%, 2.1%, and 2.6% of respondents indicating use of the 2:1 formulation and 10.9%, 15%, and 16.6% of respondents indicating use of the 4:1 formulation.
Significant AMC formulation selection variability exists across the United States.
•Clinical use cephalosporins combined with clavulanate has been scarcely described.•Oral cephalosporin/clavulanate combinations must be studied.•Clavulanate lowers MIC of cefixime/ceftibuten in ...ESBL-producing Enterobacterales.•Oral cephalosporin/clavulanate could prove a useful ESBL treatment strategy.
The use of cephalosporins combined with clavulanate for the treatment of ESBL-harbouring Enterobacteriaceae has been scarcely described. We aimed to describe the effect of different concentrations of clavulanate in the MIC of cefixime and ceftibuten of ESBL-producing Escherichia coli and Klebsiella pneumoniae.
ESBL-producing E. coli and K. pneumoniae isolates were studied. Fixed concentrations of cefixime and ceftibuten (ranges of 32–0.25 and 64–0.5 ng/ml, respectively) were used. Combinations of cefixime/clavulanate and ceftibuten/clavulanate in different ratios (1:0, 1:1, 2:1, 4:1, 8:1, 16:1, 32:1) were tested. MIC were determined by broth microdilution.
A total of 6 ESBL-producing E. coli, 6 ESBL-producing K. pneumoniae and 2 control E. coli were tested. When different quantities of clavulanate were added to cefixime and ceftibuten, greater than two-fold decreases in the MIC were observed. When testing the 1:1 cefixime/clavulanate ratio, 10/12 isolates were susceptible. When the ratios 2:1, 4:1, 8:1 and 16:1 were tested, susceptibility was noted for 9/12, 8/12, 4/12 and 5/12 isolates, respectively. Only 2/12 K. pneumoniae isolates were susceptible when the ratio 32:1 was tested. When testing ceftibuten/clavulanate, all isolates remained susceptible across all experiments.
Clavulanic acid has a favourable effect in reducing the MIC of cefixime and ceftibuten in isolates of ESBL-producing E. coli and K. pneumoniae. Combining clavulanate with ceftibuten or cefixime could be a useful treatment strategy.
Streptomyces clavuligerus: The Omics Era Liras, Paloma; Martín, Juan F
Journal of industrial microbiology & biotechnology,
12/2021, Letnik:
48, Številka:
9-10
Journal Article
Recenzirano
Odprti dostop
The Streptomyces clavuligerus genome consists in a linear chromosome of about 6.7 Mb and four plasmids (pSCL1 to pSCL4), the latter one of 1.8 Mb. Deletion of pSCL4, results in viable mutants with ...high instability in the chromosome arms, which may lead to chromosome circularisation. Transcriptomic and proteomic studies comparing different mutants with the wild-type strain improved our knowledge on the biosynthesis and regulation of clavulanic acid, cephamycin C and holomycin. Additional knowledge has been obtained on the SARP-type CcaR activator and the network of connections with other regulators (Brp, AreB, AdpA, BldG, RelA) controlling ccaR expression. The transcriptional pattern of the cephamycin and clavulanic acid clusters is supported by the binding of CcaR to different promoters and confirmed that ClaR is a CcaR-dependent activator that controls the late steps of clavulanic biosynthesis. Metabolomic studies allowed the detection of new metabolites produced by S. clavuligerus such as naringenin, desferroxamines, several N-acyl tunicamycins, the terpenes carveol and cuminyl alcohol or bafilomycin J. Heterologous expression of S. clavuligerus terpene synthases resulted in the formation of no less than 15 different terpenes, although none of them was detected in S. clavuligerus culture broth. In summary, application of the Omic tools results in a better understanding of the molecular biology of S. clavuligerus, that allows the use of this strain as an industrial actinobacterial platform and helps to improve CA production.
The honey bee has long been known to be a bioindicator of environmental pollution and the use of antimicrobials in the beekeeping industry is strictly regulated. For these reasons, this paper was ...aimed to evaluate for the first time the role of Apis mellifera as a possible indicator of environmental antimicrobial resistance (AMR). The study isolated and analysed the resistance patterns of Enterobacteriaceae from a pool of honey bee guts located in five different environmental sites (ES), where different antimicrobial selective pressures were hypothesized. In all, 48 isolates were considered for identification and underwent analyses of AMR to ampicillin, amoxicillin/clavulanic acid, cefazolin, ceftazidime, tetracycline, imipenem, enrofloxacin, amikacin and trimethoprim/sulfamethoxazole. In all, 12 isolates out of 48 (25%) showed resistance to at least one antimicrobial drug. There were no significant differences between the resistance rates observed in the ESs, even if the highest percentage of resistance was found in ES4. Resistances to amoxicillin/clavulanic acid resulted significantly higher than those detected towards the other antimicrobials. Amoxicillin/clavulanic acid is not commonly used in beekeeping but it is extensively used in animals and in humans, suggesting an environmental origin of this resistance and supporting the hypothesis that honey bees could be used as indicators of AMR spread in the environment.
Significance and Impact of the Study
In this study, a possible role of honey bees as indicator of environmental antimicrobial resistance is hypothesized. Enterobacteriaceae were isolated from bees living in different environmental sites (ES) where different antimicrobial selective pressures were hypothesized. Even if no differences between the resistances in the five ES were observed, the resistance rates for amoxicillin/clavulanic acid, compared to other antimicrobials, were significantly higher. Since amoxicillin/clavulanic acid is not used in beekeeping but it is extensively used in animals and in humans, an environmental origin of this resistance is suggested that supports our hypothesis.
Significance and Impact of the Study: In this study, a possible role of honey bees as indicator of environmental antimicrobial resistance is hypothesized. Enterobacteriaceae were isolated from bees living in different environmental sites (ES) where different antimicrobial selective pressures were hypothesized. Even if no differences between the resistances in the five ES were observed, the resistance rates for amoxicillin/clavulanic acid, compared to other antimicrobials, were significantly higher. Since amoxicillin/clavulanic acid is not used in beekeeping but it is extensively used in animals and in humans, an environmental origin of this resistance is suggested that supports our hypothesis.
The discovery of penicillin nearly 90 years ago revolutionized the treatment of bacterial disease. Since that time, numerous other antibiotics have been discovered from bacteria and fungi, or ...developed by chemical synthesis and have become effective chemotherapeutic options. However, the misuse of antibiotics has lessened the efficacy of many commonly used antibiotics. The emergence of resistant strains of bacteria has seriously limited our ability to treat bacterial illness, and new antibiotics are desperately needed. Since the discovery of penicillin, most antibiotic development has focused on the discovery of new antibiotics derived from microbial sources, or on the synthesis of new compounds using existing antibiotic scaffolds to the detriment of other lines of discovery. Both of these methods have been fruitful. However, for a number of reasons discussed in this review, these strategies are unlikely to provide the same wealth of new antibiotics in the future. Indeed, the number of newly developed antibiotics has decreased dramatically in recent years. Instead, a reexamination of traditional medicines has become more common and has already provided several new antibiotics. Traditional medicine plants are likely to provide further new antibiotics in the future. However, the use of plant extracts or pure natural compounds in combination with conventional antibiotics may hold greater promise for rapidly providing affordable treatment options. Indeed, some combinational antibiotic therapies are already clinically available. This study reviews the recent literature on combinational antibiotic therapies to highlight their potential and to guide future research in this field.
Objective
This retrospective surveillance study aimed to follow periodontitis‐associated bacterial profiles and to identify time‐dependent changes in antibiotic susceptibility patterns.
Materials and ...Methods
From 2008 to 2015, bacterial specimen from deep periodontal pockets were collected from a total of 7804 German adults diagnosed with periodontitis. Presence of selected bacteria was confirmed by anaerobic culture and nucleic acid amplification. Antimicrobial susceptibility of clinical isolates was tested by disc diffusion with antibiotics used for the treatment of periodontitis and oral infections. The prevalences of periodontal pathogens were calculated and temporal evolution of antimicrobial susceptibility towards amoxicillin, amoxicillin/clavulanic acid, metronidazole, doxycycline, clindamycin, azithromycin, ciprofloxacin and ampicillin was analysed with logistic regression.
Results
The prevalence of patients harbouring bacteria was 95.9% Fusobacterium nucleatum, 88.0% Tannerella forsythia, 76.4% Treponema denticola, 76.5%, Campylobacter rectus, 76.0% Eikenella corrodens, 75.0% Capnocytophaga spp., 68.2% Porphyromonas gingivalis, 57.7% Peptostreptococcus micros, 43.1% Prevotella intermedia, 30.4% Eubacterium nodatum and 21.5% Aggregatibacter actinomycetemcomitans. In 63.5% of patients, one or more isolates were not susceptible to at least one of the antibiotics tested. The data further revealed a trend towards decreasing susceptibility profiles (p < 0.05) with antibiotic non‐susceptibilities in 37% of patients in 2008 and in 70% in 2015.
Conclusions
The present study confirmed a high prevalence of periodontal pathogens in the subgingival microbiota of German periodontitis patients. The data revealed an incremental increase in isolates displaying resistance to some antibiotics but no relevant change in susceptibility to amoxicillin and metronidazole.
A novel antibiotic combination of the oral cephalosporin ceftibuten (CTB) and the β-lactamase inhibitor clavulanate (CLA) is currently in development for urinary tract infections, including those ...caused by extended-spectrum-β-lactamase (ESBL)-producing organisms. This study aimed to identify the pharmacodynamic index and magnitude of this index for CLA, when combined with a fixed CTB exposure (∼59% free time above the CTB-CLA MIC) against ESBL-producing
and
(CTB-CLA MICs of 0.25/0.125 to 1/0.5 μg/ml) using the
chemostat model. Dose fractionation studies identified the time that free CLA concentrations remained above a threshold concentration (
>threshold) to be the best pharmacodynamic index (
= 0.85) compared with the free area under the curve (AUC)/threshold ratio (
= 0.62) and free maximum concentration/threshold ratio (
= 0.37). For
isolates, stasis and 1-log
CFU reductions were achieved at 30.9 and 47.9%
>CTB concentrations of the 2:1 CTB-CLA MIC (
>MIC here), respectively. For
isolates, stasis and 1-log
CFU reductions were achieved at 51.9 and 92.0%
>MIC, respectively. These data inform exposure requirements for CLA combined with CTB for optimizing pharmacodynamics against
and should be useful in designing dosage regimens for this combination antibiotic.
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