Amoxicillin-Clavulanate Breakpoints Against Enterobacterales: Rationale for Revision by the Clinical and Laboratory Standards Institute.

Amoxicillin-clavulanate (AMC) is among the most frequently prescribed antibiotics globally. It has broad antibacterial activity against gram-positive, gram-negative, and anaerobic bacteria and has been used to treat infections caused by a broad range of pathogens. AMC breakpoints against Enterobacterales were initially set in the 1980s. However, since that time, increases in antibiotic resistance, advances in pharmacokinetic/pharmacodynamic analyses, and publication of additional clinical data prompted a reassessment by the Clinical and Laboratory Standards Institute (CLSI) Subcommittee on Antimicrobial Susceptibility Testing. Based on this contemporary reappraisal, the CLSI retained the Enterobacterales breakpoints but revised comments regarding dosing associated with use of the AMC breakpoints in the 2022 supplement of M100. This viewpoint provides insight into the CLSI breakpoint reevaluation process and summarizes the data and rationale used to support these revisions to the AMC Enterobacterales breakpoint.

Identification of Reduced ERAP2 Expression and a Novel HLA Allele as Components of a Risk Score for Susceptibility to Liver Injury Due to Amoxicillin-Clavulanate.

BACKGROUND & AIMS: Drug-induced liver injury (DILI) due to amoxicillin-clavulanate (AC) has been associated with HLA-A∗02:01, HLA-DRB1∗15:01, and rs2476601, a missense variant in PTPN22. The aim of this study was to identify novel risk factors for AC-DILI and to construct a genetic risk score (GRS). METHODS: Transcriptome-wide association study and genome-wide association study analyses were performed on 444 AC-DILI cases and 10,397 population-based controls of European descent. Associations were confirmed in a validation cohort (n = 133 cases and 17,836 population-based controls). Discovery and validation AC-DILI cases were also compared with 1358 and 403 non-AC-DILI cases. RESULTS: Transcriptome-wide association study revealed a significant association of AC-DILI risk with reduced liver expression of ERAP2 (P = 3.7 × 10-7), coding for an aminopeptidase involved in antigen presentation. The lead eQTL single nucleotide polymorphism, rs1363907 (G), was associated with AC-DILI risk in the discovery (odds ratio [OR], 1.68; 95% CI, 1.23-1.66; P = 1.7 × 10-7) and validation cohorts (OR, 1.2; 95% CI, 1.04-2.05; P = .03), following a recessive model. We also identified HLA-B∗15:18 as a novel AC-DILI risk factor in both discovery (OR, 4.19; 95% CI, 2.09-8.36; P = 4.9 × 10-5) and validation (OR, 7.78; 95% CI, 2.75-21.99; P = .0001) cohorts. GRS, incorporating rs1363907, rs2476601, HLA-B∗15:18, HLA-A∗02:01, and HLA-DRB1∗15:01, was highly predictive of AC-DILI risk when cases were analyzed against both general population and non-AC-DILI control cohorts. GRS was the most significant predictor in a regression model containing known AC-DILI clinical risk characteristics and significantly improved the predictive model. CONCLUSIONS: We identified novel associations of AC-DILI risk with ERAP2 low expression and with HLA-B∗15:18. GRS based on the 5 risk variants may assist AC-DILI causality assessment and risk management.

Idiosyncratic Drug-Induced Liver Injury and Amoxicillin-Clavulanate: Spotlight on Gut Microbiota, Fecal Metabolome and Bile Acid Profile in Patients.

Several hepatic disorders are influenced by gut microbiota, but its role in idiosyncratic drug-induced liver injury (iDILI), whose main causative agent is amoxicillin-clavulanate, remains unknown. This pioneering study aims to unravel particular patterns of gut microbiota composition and associated metabolites in iDILI and iDILI patients by amoxicillin-clavulanate (iDILI-AC). Thus, serum and fecal samples from 46 patients were divided into three study groups: healthy controls (n = 10), non-iDILI acute hepatitis (n = 12) and iDILI patients (n = 24). To evaluate the amoxicillin-clavulanate effect, iDILI patients were separated into two subgroups: iDILI non-caused by amoxicillin-clavulanate (iDILI-nonAC) (n = 18) and iDILI-AC patients (n = 6). Gut microbiota composition and fecal metabolome plus serum and fecal bile acid (BA) analyses were performed, along with correlation analyses. iDILI patients presented a particular microbiome profile associated with reduced fecal secondary BAs and fecal metabolites linked to lower inflammation, such as dodecanedioic acid and pyridoxamine. Moreover, certain taxa like Barnesiella, Clostridia UCG-014 and Eubacterium spp. correlated with significant metabolites and BAs. Additionally, comparisons between iDILI-nonAC and iDILI-AC groups unraveled unique features associated with iDILI when caused by amoxicillin-clavulanate. In conclusion, specific gut microbiota profiles in iDILI and iDILI-AC patients were associated with particular metabolic and BA status, which could affect disease onset and progression.

Weak direct current exerts synergistic effect with antibiotics and reduces the antibiotic resistance: An in vitro subgingival plaque biofilm model.

BACKGROUND AND OBJECTIVE: Weak direct current (DC) exerts killing effect and synergistic killing effect with antibiotics in some specific bacteria biofilms. However, the potential of weak DC alone or combined with periodontal antibiotics in controlling periodontal pathogens and plaque biofilms remains unclear. The objective of this study was to investigate whether weak DC could exert the anti-biofilm effect or enhance the killing effect of metronidazole (MTZ) and/or amoxicillin-clavulanate potassium (AMC) on subgingival plaque biofilms, by constructing an in vitro subgingival plaque biofilm model. METHODS: The pooled subgingival plaque and saliva of patients with periodontitis (n = 10) were collected and cultured anaerobically on hydroxyapatite disks in vitro for 48 h to construct the subgingival plaque biofilm model. Then such models were stimulated with 0 µA DC alone (20 min/12 h), 1000 µA DC alone (20 min/12 h), 16 µg/ml MTZ, 16 µg/ml AMC or their combination, respectively. Through viable bacteria counting, metabolic activity assay, quantitative real-time PCR absolute quantification and 16S rDNA sequencing analysis, the anti-biofilm effect of 1000 µA DC and enhanced killing effects of 1000 µA DC combined with antibiotics (MTZ, AMC or MTZ+AMC) were explored. RESULTS: The old subgingival plaque model (48 h) had no significant difference in total bacterial loads from subgingival plaque in situ, which achieved a similarity of 80%. The 1000 µA DC plus MTZ or AMC for 12 h showed a stronger synergistic killing effect than the same combination for 20 min. The metabolic activity was reduced to the lowest by DC plus MTZ+AMC, as 37.4% of that in the control group, while average synergistic killing effect reached 1.06 log units and average total bacterial loads decreased to 0.87 log units. Furthermore, the relative abundance of the genera Porphyromonas, Prevotella, Treponema_2, and Tannerella were decreased significantly. CONCLUSION: The presence of weak DC (1000 µA) improved the killing effect of antibiotics on subgingival plaque biofilms, which might provide a novel strategy to reduce their antibiotic resistance.

Oral amoxicillin/clavulanate for the prevention of bacteremia following dental extractions.

This study aimed to evaluate the effectiveness of oral amoxicillin/clavulanate (AMX-CL) for the prevention of bacteremia following dental extractions. The study group (AMX-CLG) comprised 40 adults requiring dental extractions under general anesthesia who were administered a prophylactic regimen of 1875/125 mg of AMX-CL orally 1-2 h prior to the surgery. Venous blood samples were collected from each patient at baseline and at 30 s and 15 min after dental extractions. Samples were inoculated into BACTEC Plus culture bottles and processed in the BACTEC 9240. Conventional microbiological techniques were used for subcultures and further identification of the isolated bacteria. The results for the AMX-CLG were compared with those of a control group (CG; no prophylaxis) and an amoxicillin group (AMXG; 2 g of amoxicillin orally), consisting of randomly selected patients from among those participating in two clinical trials that we have previously published. The prevalence of bacteremia in the CG, AMXG, and AMX-CLG was 97%, 50%, and 15%, respectively, at 30 s after completing the extractions, and 67%, 10%, and 4% at 15 min, respectively, after the last extraction. The prevalence of bacteremia in the AMXG and the AMX-CLG at 30 s and at 15 min after completing the extractions was significantly lower than that in the CG (p < 0.001 and p < 0.001, respectively; Fisher's exact test). The prevalence of bacteremia in the AMX-CLG at 30 s after completing the extractions was significantly lower than that in the AMXG (p < 0.001; Fisher's exact test). Based in the results of this preliminary study, oral AMX-CL could be an excellent option for preventing bacteremia secondary to dental procedures in patients at risk.

Antibiotic associated diarrhea in outpatient pediatric antibiotic therapy.

BACKGROUND: Antibiotic-associated diarrhea is one of the most frequent side effects of antimicrobial therapy. We assessed the epidemiological data of antibiotic-associated diarrhea in pediatric patients in our region. METHODS: The prospective multi-center study included pediatric patients who were initiated an oral antibiotic course in outpatient clinics and followed in a well-established surveillance system. This follow-up system constituded inclusion of patient by the primary physician, supply of family follow-up charts to the family, passing the demographics and clinical information of patient to the Primary Investigator Centre, and a close telephone follow-up of patients for a period of eight weeks by the Primary Investigator Centre. RESULTS: A result of 758 cases were recruited in the analysis which had a frequency of 10.4% antibiotic-associated diarrhea. Among the cases treated with amoxicillin-clavulanate 10.4%, and cephalosporins 14.4% presented with antibiotic-associated diarrhea. In the analysis of antibiotic-associated diarrhea occurrence according to different geographical regions of Turkey, antibiotic-associated diarrhea episodes differed significantly (p = 0.014), particularly higher in The Eastern Anatolia and Southeastern Anatolia. Though most commonly encountered with cephalosporin use, antibiotic-associated diarrhea is not a frequent side effect. CONCLUSION: This study on pediatric antibiotic-associated diarrhea displayed epidemiological data and the differences geographically in our region.

Evaluation of Amoxicillin and Amoxicillin-Clavulanate (Augmentin) for Antimicrobial Postexposure Prophylaxis Following Bacillus anthracis Inhalational Exposure in Cynomolgus Macaques.

Amoxicillin is a broad-spectrum antibiotic used to treat a variety of gram-positive and gram-negative infections, such as infections of the ear, nose, and throat, genitourinary tract, skin, and lower respiratory tract; gonorrhea; and Helicobacter pylori. The prophylactic benefit of both amoxicillin and Augmentin (amoxicillin-clavulanate for use against ß-lactamase-expressing bacteria) was evaluated for inhalation anthrax in cynomolgus macaques in 2 studies. A pilot study on amoxicillin-clavulanate that used a portion of the study animals demonstrated empirically that dosing twice a day was efficacious. In a subsequent study on both amoxicillin and amoxicillin-clavulanate that used the remaining study animals, the animals were treated orally every 12 hours on days 1-28 postchallenge and followed for an additional 60 days (total of 88 days from day of aerosol challenge to when the animals were culled). The animals from each treatment arm of the 2 studies were completely protected. All untreated animals succumbed to the infection. The degree of protection observed in this study suggests that both amoxicillin and amoxicillin-clavulanate, administered prophylactically over a period of 28 days after a lethal exposure to Bacillus anthracis spores, is sufficient for full protection.

Results of penicillin skin testing in patients with suspected penicillin allergy - the Qatar experience.

BACKGROUND: Unverified penicillin allergy has been linked to adverse patient events and increased healthcare expenditure owing to the usage of broad-spectrum, expensive antibiotics. Penicillin allergy test is the gold standard to diagnose penicillin allergy; and in this study, we present data from Qatar which have not been published before. METHODS: Patients with a history of penicillin allergy who underwent penicillin allergy testing between January 2015 and December 2020 at the Allergy Division of the Hamad General Hospital were retrospectively reviewed from the division registry. Benzylpenicilloyl-polylysine (PPL) and minor determinant mixture (MDM) kit DAP-penicillin (0.04 mg +0.5 mg)/vial) (penicillin G, amoxicillin (20 mg/vial), and lately clavulanic acid (20 mg/vial) (DAP, Diater, Madrid, Spain) were used for skin and intradermal testing according to published guidelines. Patients with negative skin tests were administered direct oral challenge with amoxicillin/clavulanate (500/125 mg) and observed for 2 hours. RESULTS: Of the 189 charts reviewed, 183 patients had a complete data set for analysis. Patients were predominantly women (n = 132, 72%) with an average age of 42 years. Of these patients, 149 (81.4%) had a history of an immediate allergic reaction to penicillin, 10 had a history of delayed reactions, and 24 had other or undefined reactions. A total of 39 (21.3%) patients were diagnosed with penicillin allergy (30 patients with positive skin test results and 9 using a direct oral challenge). Of the 30 patients with positive skin testing, 5 reacted to PPL, 8 to MDM, 13 to amoxicillin, and 4 to clavulanic acid. CONCLUSION: Previous studies indicate that 90% patients with a history of penicillin allergy were able to tolerate the drug (10% were truly allergic). Our data showed that 21% were truly allergic to penicillin. This high positive rate can be attributed to the high pretest probability based on the detailed history obtained before the test, which led to the exclusion of patients with symptoms incompatible with penicillin allergy from the test.

Efficacy and safety of azithromycin and amoxicillin/clavulanate for otitis media in children: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Resistance, prolonged therapy, and more adverse reactions made amoxicillin less preferred for treating otitis media. This study aimed to compare the efficacy and safety of azithromycin and amoxicillin/clavulanate for the treatment of otitis media in children. METHODOLOGY: This study was a systematic review and meta-analysis. PubMed, Cochrane library, and Google scholar databases were searched. Comparative randomized clinical trial studies between azithromycin and amoxicillin/clavulanate to treat otitis media in children published up to 30 September 2019 were included. The risk of bias was assessed and Data was extracted by the first author and checked by the second author. Meta-analysis was performed by STATA software version 16, and Mantel-Haenszel statistical method with effect measure odds ratio was employed for analysis. RESULT: 751 records were identified and 14 studies were eligible for analysis. In 12 studies azithromycin had equivalent clinical efficacy and 2 had less to amoxicillin/clavulanate. Meta-analysis results showed no statistically significant difference in efficacy in favor of amoxicillin/clavulanate after completion of treatment OR 0.75, 95% CI (0.62-0.91). On subgroup analysis for children less than 2 years (OR 0.96 95% CI (0.49-2.29), and greater than 2 years (OR 1.40 95% CI (0.93-2.11) and also efficacy on follow up (OR 0.97 95% CI (0.83-1.15) there is no statistically significant difference. The clinical adverse events are more in the amoxicillin/clavulanate group than in the azithromycin with a statistical significant difference OR 0.46 95% CI (0.43-0.56). CONCLUSION: Azithromycin is comparable to amoxicillin/clavulanate to treat otitis media in children, and it is safer and more tolerable.

Children with acute pyelonephritis need medical re-evaluation when home-treated with oral antibiotics.

AIM: To investigate the efficacy and safety of home-treatment with oral piv-mecillinam or amoxicillin-clavulanate in children with acute pyelonephritis. METHODS: Children aged over 6 months diagnosed with culture confirmed pyelonephritis at Danish Paediatric Departments were home-treated with piv-mecillinam (tablets) or amoxicillin-clavulanate (liquid or tablets). Follow-up was performed by phone (second treatment day) and clinical review of the patients in the hospital (day three). RESULTS: Four hundred eighteen children were included. In total, 333/418 (80%) responded well to the initial oral antibiotic treatment. 85/418 (20%) were changed to another treatment of these 47/418 (11%) to a second-line oral antibiotic and 38/418 (9%) to intravenous antibiotics due to insufficient clinical improvement or bacterial resistance. Bacterial resistance was similar for piv-mecillinam and amoxicillin-clavulanate: 4/74 (5%) versus 33/333 (10%) (p = 0.22). Insufficient clinical improvement, despite no resistance, primarily occurred in children treated with piv-mecillinam: 16/74 (22%) versus 28/344 (8%) (p < 0.001), and predominantly occurred in piv-mecillinam treated children <5 years: 7/20 (35%) versus 9/54 (17%) (p < 0.05), potentially because of problems with piv-mecillinam tablets. In the study population no cases of death or septicemia developed after start of initial oral treatment. CONCLUSION: A home-treatment regime for pyelonephritis in children >6 months is safe; however, during treatment, clinical re-evaluation is required as in 20% of cases a change in treatment was necessary.

Adverse Events of Antibiotics Used to Treat Acute Otitis Media in Children: A Systematic Meta-Analysis.

OBJECTIVE: To characterize the incidence of adverse events (AEs) associated with antibiotics used to treat acute otitis media in children. STUDY DESIGN: We searched MEDLINE for studies conducted between January 1, 1966, and August 25, 2018. Two authors independently assessed potential studies and extracted the data. We included published randomized controlled trials, cross-sectional studies, and cohort studies that evaluated the incidence of diarrhea, generalized rash, diaper rash, and candidal diaper dermatitis associated with the use of amoxicillin, amoxicillin/clavulanate, azithromycin, cefdinir, and placebo in children with acute otitis media. RESULTS: We included 82 studies in the meta-analysis. The incidence of diarrhea, listed from lowest to highest, was azithromycin (2.2%), placebo (6.9%), low-dose amoxicillin (8.7%), cefdinir (13.0%), high-dose amoxicillin (13.8%), and high-dose amoxicillin/clavulanate (18.9%). The incidence of generalized rash, listed from lowest to highest, was azithromycin (1.4%), placebo (2.3%), low-dose amoxicillin (2.9%), high-dose amoxicillin/clavulanate (4.9%), and high-dose amoxicillin (6.5%). In studies of low-dose amoxicillin, we found a higher incidence of diarrhea in studies that used daily diaries to collect information about diarrhea and a lower incidence of generalized rash in studies that reported only rashes judged to be secondary to antibiotic use. CONCLUSIONS: The incidence of AEs varies widely depending on which antibiotic is used and how the information on AEs was collected or reported. The AEs rates reported here may be helpful to clinicians when choosing an antibiotic to treat acute otitis media.

Toxicity of some broad-spectrum antibacterials in normal rat liver: the role of mitochondrial membrane permeability transition pore.

Ciprofloxacin (CIP) and Amoxycillin/Clavulanate (AC) are broad-spectrum antibiotics that are commonly administered for treatment of various bacterial infections. Studies have reported the antiproliferative and apoptotic activities of CIP in several cancer cell lines while AC has been implicated in drug-induced liver injury. We investigated the influence of CIP and AC on mitochondrial Permeability Transition (mPT) pore, ATPase activity, and cytochrome C release of normal Rat Liver Mitochondria (RLM) spectrophotometrically. In vitro, CIP and AC induced the opening of the mPT pore in a concentration-dependent manner with evidence of cytochrome C release maximally at 70 µg/ml by 13 and 10 folds, respectively. In vivo, CIP (100, 200 mg/kgbw) significantly induced mPT pore opening with induction folds of 2.4 and 2.6, respectively. However, low dose of AC (10 mg/kgbw) had no effect whatsoever on the mPT pore while higher dose (30 mg/kgbw) significantly induced pore opening by 3.4 folds. Similarly, CIP(100 mg/kgbw) and AC (30 mg/kgbw), significantly enhanced RLM ATPase activity, induced cytochrome C release and increased levels of RLM malondialdehyde generation and triggered the activation of caspases-9 and 3 in liver post-mitochondrial fraction. There were also significant (p<0.05) elevation in levels of serum aminotransferases and white blood cell count. Our results show that prolonged use of Ciprofloxacin and Amoxicillin Clavulanate could result in mitochondrial membrane breakdown via induction of opening of mPT pore leading to expulsion of cytochrome C, lipid peroxidation and decrease in energy content in healthy liver cells. These drugs should therefore be used with caution.

Reduced-Concentration Clavulanate for Young Children with Acute Otitis Media.

Amoxicillin-clavulanate (A/C) is currently the most effective oral antimicrobial in treating children with acute otitis media (AOM), but the standard dosage of 90 mg amoxicillin/6.4 mg clavulanate/kg of body weight/day commonly causes diarrhea. We examined whether an A/C formulation containing lower concentrations of clavulanate would result in less diarrhea while maintaining plasma levels of amoxicillin and clavulanate adequate to eradicate middle-ear pathogens and to achieve clinical success. We conducted an open-label study in children with AOM who were 6 to 23 months of age. In phase 1, we treated 40 children with a reduced-clavulanate A/C formulation providing 90 mg amoxicillin/3.2 mg clavulanate/kg/day for 10 days. In phase 2, we treated 72 children with the same formulation at a dosage of 80 mg amoxicillin/2.85 mg clavulanate/kg/day for 10 days. We compared the rates of protocol-defined diarrhea (PDD), diaper dermatitis, and AOM clinical response in these children with rates we had reported in children who received the standard A/C regimen, and we obtained plasma levels of amoxicillin and clavulanate at various time points. Outcomes in phase 1 children and in children who had received the standard regimen did not differ significantly. Rates of PDD in children receiving phase 2 and standard regimens were 17% and 26%, respectively (P = 0.10). The corresponding rates of diaper dermatitis were 21% and 33% (P = 0.04) and of AOM treatment failure were 12% and 16% (P = 0.44). Symptomatic responses did not differ significantly between regimens; both gave clavulanate levels sufficient to inhibit ß-lactamase activity. In young children with AOM, clavulanate dosages lower than those currently used may be associated with fewer side effects without reducing clinical efficacy. (This study has been registered at ClinicalTrials.gov under registration no. NCT02630992.).

Performance of EUCAST and CLSI approaches for co-amoxiclav susceptibility testing conditions for clinical categorization of a collection of Escherichia coli isolates with characterized resistance phenotypes.

OBJECTIVES: There are different methodological recommendations for in vitro testing of the co-amoxiclav combination. Performance of co-amoxiclav MIC testing for Escherichia coli by the standard ISO microdilution method (ISO 20776-1) was compared using EUCAST (fixed 2 mg/L clavulanate concentration) and CLSI (2 : 1 ratio) interpretive criteria. METHODS: MICs were determined by broth microdilution using a 2 : 1 ratio and fixed clavulanate concentrations (2 and 4 mg/L) for 160 clinical E. coli isolates with characterized resistance mechanisms. Essential agreements, categorical agreements and relative errors were determined. RESULTS: For all isolates, essential agreement between microdilution using 2 mg/L clavulanate and a 2 : 1 ratio was 25.6%. For ESBL-producing isolates, considering EUCAST breakpoints, 55% of isolates tested with 2 mg/L clavulanate were classified as resistant; conversely, 95% of isolates tested with 4 mg/L clavulanate were susceptible. When using CLSI breakpoints and a 2 : 1 ratio, 90% of isolates were susceptible and 10% were intermediate. CONCLUSIONS: Variation in the clavulanate concentration gave different susceptibility testing results, particularly among ESBL-producing E. coli isolates. The in vitro concentration of clavulanate that better correlates with clinical outcome is still under debate and should be established.

Rectal pre-treatment with ozonized oxygen (O3) aggravates clinic status in septic rats treated with amoxicillin/clavulanate.

INTRODUCTION: Despite the advanced antibiotic therapies, sepsis continues being a clinical entity with high morbidity and mortality. The ozone/oxygen mixture (O3/O2) has been reported to exhibit positive effects on immunity. The aim of our study was to analyze whether (O3/O2) combined with amoxicillin/clavulanate has any influence on the morbidity and mortality of septic rats. METHODS: We used 48 Sprague-Dawley rats randomly allocated to 6 groups (n=8): healthy (C), septic (I), healthy+ozone therapy (O3), septic+amoxicillin/clavulanate (AMC), septic+amoxicillin/clavulanate+ozone therapy (AMC/O3) and septic+ozone therapy (I/O3). O3/O2 was administered rectally at increasing O3 concentrations during 10 days prior to the onset of sepsis model (intraperitoneally injection of fecal material) or saline administration in healthy control rats. Later (post-inoculation), 3 days per week, O3 was also administered. Vital signs were recorded, and microbiological, hematological and histopathological studies were performed. RESULTS: The number of surviving animal/total was higher in AMC (8/8) than in AMC/O3 (4/8) p=0.077. The percentage of surviving animals with pneumonia was higher in AMC/O3 than in AMC (100% vs 37.5%). In dead animals, AMC/O3 rats had a significantly higher percentage of lesions: Cardiac lesions, pulmonary hemorrhages and pleuritis (100%) and serositis/peritonitis (75%). Only Escherichia coli (2 different biotypes) was isolated from blood and/or peritoneal fluid from all infected groups. A significant decrease in the percentage of band neutrophils from the surviviors belonging to AMC/O3vs AMC was observed (p<0.05). CONCLUSION: Rectal pre-treatment with O3/O2 aggravates clinic status in septic rats treated with amoxicillin/clavulanate.

ß-lactamases produced by amoxicillin-clavulanate-resistant enterobacteria isolated in Buenos Aires, Argentina: a new blaTEM gene.

Resistance to ß-lactam/ß-lactamase inhibitors in enterobacteria is a growing problem that has not been intensively studied in Argentina. In the present work, 54/843 enterobacteria collected in a teaching hospital of Buenos Aires city were ampicillin-sulbactam-resistant isolates remaining susceptible to second- and third-generation cephalosporins. The enzymatic mechanisms present in the isolates, which were also amoxicillin-clavulanic acid (AMC)-resistant (18/54) were herein analyzed. Sequencing revealed two different variants of blaTEM-1, being blaTEM-1b the most frequently detected allelle (10 Escherichia coli, 3 Klebsiella pneumoniae, 2 Proteus mirabilis and 1 Raoultella terrigena) followed by blaTEM-1a (1 K. pneumoniae). Amoxicillin-clavulanate resistance seems to be mainly associated with TEM-1 overproduction (mostly in E. coli) or co-expressed with OXA-2-like and/or SHV ß-lactamases (K. pneumoniae and P. mirabilis). A new blaTEM variant (TEM-163) was described in an E. coli strain having an AMC MIC value of 16/8µg/ml. TEM-163 contains Arg275Gln and His289Leu amino acid substitutions. On the basis of the high specific activity and low IC50 for clavulanic acid observed, the resistance pattern seems to be due to overproduction of the new variant of broad spectrum ß-lactamase rather than to an inhibitor-resistant TEM (IRT)-like behavior.

Susceptibility of clinical Moraxella catarrhalis isolates in British Columbia to six empirically prescribed antibiotic agents.

BACKGROUND: Moraxella catarrhalis is a commensal organism of the respiratory tract that has emerged as an important pathogen for a variety of upper and lower respiratory tract infections including otitis media and acute exacerbations of chronic bronchitis. Susceptibility testing of M catarrhalis is not routinely performed in most diagnostic laboratories; rather, a comment predicting susceptibility based on the literature is attached to the report. The most recent Canadian report on M catarrhalis antimicrobial susceptibility was published in 2003; therefore, a new study at this time was of interest and importance. OBJECTIVE: To determine the susceptibility of M catarrhalis isolates from British Columbia to amoxicillin-clavulanate, doxycycline, clarithromycin, cefuroxime, levofloxacin and trimethoprimsulfamethoxazole. METHODS: A total of 117 clinical M catarrhalis isolates were isolated and tested from five Interior hospitals and two private laboratory centres in British Columbia between January and December 2012. Antibiotic susceptibility of M catarrhalis isolates was characterized using the Etest (E-strip; bioMérieux, USA) according to Clinical Laboratory Standards Institute guidelines. RESULTS: All isolates were sensitive to amoxicillin-clavulanate, doxycycline, clarithromycin, levofloxacin and trimethoprimsulfamethoxazole. One isolate was intermediately resistant to cefuroxime, representing a 99.15% sensitivity rate to the cephem agent. Cefuroxime minimum inhibitory concentrations (MICs) inhibiting 50% and 90% of organisms (MIC50 and MIC90) were highest among the antibiotics tested, and the MIC90 (3 µg/mL) of cefuroxime reached the Clinical Laboratory Standards Institute breakpoint of susceptibility. DISCUSSION: The antibiotic susceptibility of M catarrhalis isolates evaluated in the present study largely confirms the findings of previous surveillance studies performed in Canada. Cefuroxime MICs are in the high end of the sensitive range and the MIC50 and MIC90 observed in the present study are the highest ever reported in Canada. CONCLUSION: Although cefuroxime MICs in M catarrhalis are high, all agents tested showed antimicrobial activity, supporting their continued therapeutic and empirical use.

HISTORIQUE: Le Moraxella catarrhalis est un organisme commensal des voies respiratoires, qui se révèle un pathogène important dans diverses infections des voies respiratoires supérieures et inférieures, y compris l'otite moyenne et les exacerbations aiguës de la bronchite chronique. Dans la plupart des laboratoires diagnostiques, les tests de susceptibilité au M catarrhalis ne sont pas effectués systématiquement. Un commentaire en prédisant la susceptibilité d'après les publications est joint au rapport. Le dernier rapport canadien sur la susceptibilité du M catarrhalis aux antimicrobiens a été publié en 2003. Il est donc judicieux et important de publier une nouvelle étude à ce sujet. OBJECTIF: Déterminer la susceptibilité des isolats de M catarrhalis provenant de la Colombie-Britannique à l'amoxicilline-clavulanate, à la doxycycline, à la clarithromycine, à la céfuroxime, à la lévofloxacine et au triméthoprime-sulfaméthoxazole. MÉTHODOLOGIE: Au total, 117 isolats cliniques de M catarrhalis provenant de cinq hôpitaux de l'intérieur et de deux laboratoires privés de la Colombie-Britannique ont été prélevés et examinés entre janvier et décembre 2012. Les chercheurs ont caractérisé la susceptibilité aux antibiotiques des isolats de M catarrhalis au moyen de l'Etest (E-strip; bioMérieux, États-Unis), conformément aux lignes directrices du Clinical Laboratory Standards Institute. RÉSULTATS: Tous les isolats étaient sensibles à l'amoxicillineclavulanate, à la doxycycline, à la clarithromycine, à la lévofloxacine et au triméthoprime-sulfaméthoxazole. Un isolat était moyennement résistant à la céfuroxime, représentant un taux de sensibilité de 99,15 % à l'agent céphème. Les concentrations minimales inhibitrices (CMI) de la céfuroxime inhibant 50 % et 90 % des organismes (CMI50 et CMI90) étaient les plus élevées des antibiotiques à l'étude, et la CMI90 (3 µg/mL) de la céfuroxime atteignait le seuil de susceptibilité du Clinical Laboratory Standards Institute. EXPOSÉ: La susceptibilité des isolats de M catarrhalis aux antibiotiques évalués dans la présente étude confirme largement les observations tirées d'études de surveillance antérieures effectuées au Canada. Les CMI de la céfuroxime se situent dans la plage supérieure de sensibilité. De plus, la CMI50 et la CMI90 observées dans la présente étude sont les plus élevées jamais déclarées au Canada. CONCLUSION: Même si les CMI de la céfuroxime dans les isolats de M catarrhalis sont élevées, tous les agents étudiés présentaient une activité antimicrobienne, ce qui appuie la poursuite de leur utilisation dans un cadre thérapeutique et empirique.

Evaluation of Oral Amoxicillin/Clavulanate for Urinary Tract Infections Caused by Ceftriaxone Non-Susceptible Enterobacterales.

Urinary tract infections (UTIs) are one of the most common infections and are frequently caused by Gram-negative organisms. The rise of resistant isolates has prompted evaluation of alternative therapies, including amoxicillin-clavulanate which has potent activity against Ambler class A enzymes. This study sought to evaluate clinical outcomes of patients with ceftriaxone non-susceptible UTIs receiving amoxicillin-clavulanate or standard of care (SOC). This was a single-center, retrospective, cohort study of adult patients with urinary tract infections caused by a ceftriaxone non-susceptible pathogen who received amoxicillin-clavulanate or SOC. The primary outcome was clinical failure at 90 days. Secondary outcomes included time to failure, isolation of a resistant organism, and hospital length of stay. Fifty-nine patients met study inclusion: 26 received amoxicillin/clavulanate and 33 received SOC. Amoxicillin-clavulanate recipients did not have higher failure rates compared to SOC recipients. For patients requiring hospital admission, hospital length of stay was numerically shorter with amoxicillin-clavulanate. The frequency of amoxicillin-clavulanate and carbapenem-resistant organisms did not differ significantly between groups. Amoxicillin-clavulanate may be a useful alternative therapy for the treatment of ceftriaxone non-susceptible Enterobacterales UTIs.

VRE acquisition in hospital and its association with hospital antimicrobial usage -a non-linear analysis of an extended time series.

BACKGROUND: Vancomycin resistant enterococci (VRE) have become endemic pathogens in many Australian hospitals causing significant morbidity. There are few observational studies that have evaluated the effect of antibiotic usage on VRE acquisition. This study examined VRE acquisition and its association with antimicrobial use. The setting was a NSW tertiary hospital with 800 beds over a 63 month period up to March 2020, straddling piperacillin-tazobactam (PT) shortages that occurred from in September 2017. METHODS: The primary outcome was monthly inpatient hospital onset Vancomycin-resistant Enterococci (VRE) acquisitions. Multivariate adaptive regression splines (MARS) were used to estimate hypothetical thresholds, where antimicrobial use above threshold is associated with increased incidence of hospital onset VRE acquisition. Specific antimicrobials and categorised usage (broad, less broad and narrow spectrum) were modelled. RESULTS: There were 846 hospital onset VRE detections over the study period. Hospital onset vanB and vanA VRE acquisitions fell significantly by 64% and 36% respectively after the PT shortage. MARS modelling indicated that PT usage was the only antibiotic found to exhibit a meaningful threshold. PT usage greater than 17.4 defined daily doses/1000 occupied bed-days (95%C I: 13.4, 20.5) was associated with higher onset of hospital VRE. CONCLUSIONS: This paper highlights the large, sustained impact that reduced broad spectrum antimicrobial use had on VRE acquisition and showed that PT use in particular was a major driver with a relatively low threshold. It raises the question as to whether hospitals should be determining local antimicrobial usage targets based on direct evidence from local data analysed with non-linear methods.