MIC Data Research Articles

Identification of antibiotic collateral sensitivity and resistance interactions in population surveillance data.

BackgroundCollateral effects of antibiotic resistance occur when resistance to one antibiotic agent leads to increased resistance or increased sensitivity to a second agent, known respectively as collateral resistance (CR) and collateral sensitivity (CS). Collateral effects are relevant to limit impact of antibiotic resistance in design of antibiotic treatments. However, methods to detect antibiotic collateral effects in clinical population surveillance data of antibiotic resistance are lacking.ObjectivesTo develop a methodology to quantify collateral effect directionality and effect size from large-scale antimicrobial resistance population surveillance data.MethodsWe propose a methodology to quantify and test collateral effects in clinical surveillance data based on a conditional t-test. Our methodology was evaluated using MIC data for 419 Escherichia coli strains, containing MIC data for 20 antibiotics, which were obtained from the Pathosystems Resource Integration Center (PATRIC) database.ResultsWe demonstrate that the proposed approach identifies several antibiotic combinations that show symmetrical or non-symmetrical CR and CS. For several of these combinations, collateral effects were previously confirmed in experimental studies. We furthermore provide insight into the power of our method for multiple collateral effect sizes and MIC distributions.ConclusionsOur proposed approach is of relevance as a tool for analysis of large-scale population surveillance studies to provide broad systematic identification of collateral effects related to antibiotic resistance, and is made available to the community as an R package. This method can help mapping CS and CR, which could guide combination therapy and prescribing in the future.

Correction for Oh et al., "Development of a Broth Microdilution Method for Exebacase Susceptibility Testing".

Volume 65, no. 7, e02587-20, 2021, https://doi.org/10.1128/AAC.02587-20. In Table 4, a single methicillin-susceptible Staphylococcus aureus isolate inhibited by 0.12 μg/ml of exebacase is presented, and the remaining 148 isolates tested have an exebacase MIC range of 0.25 to 1 μg/ml. Further investigation of the isolate with an exebacase MIC of 0.12 μg/ml to confirm bacterial identification (by MALDI-TOF) and MIC revealed the isolate to be Staphylococcus pseudintermedius. Based on this finding, the authors wish to correct Table 4 and the corresponding text that refers to the S. aureus MIC data accordingly. With these corrections, the interpretation and conclusions of the article remain the same.

Molecular modelling, synthesis and antimicrobial evaluation of benzimidazole nucleoside mimetics

A series of new N-1-(β-d-ribofuranosyl) benzimidazole derivatives has been designed using in silico methods and synthesized as probable antimicrobial agents. Further, the compounds were assessed for their antibacterial and antifungal activity. Antibacterial screening was done by employing broth micro-dilution method and compounds exhibited excellent inhibitory activity (MIC, 50–1.56 µg/mL) against different human pathogenic bacteria, viz. B. cerus, B. subtilis, S. aureus, E. coli and P. aeruginosa and drug resistant strain (DRS) of E. coli. A great synergistic effect was observed during evaluation of ∑FIC, where a combination study was performed using standard references, viz. chloramphenicol and kanamycin. The MIC data obtained from different methods of combination approach revealed 4–128 fold more potency compared to compounds tested alone. The results clearly indicated the possibility of these compounds as active ingredients of drug regimen used against MDR strains. Antifungal screening were also performed employing two different methods, viz. serial dilution method and zone inhibition method, clearly indicated that compounds were also potentially active against several species of pathogenic fungal strains, viz. A. flavus, A. niger, F. oxysporum and C. albicans. The assessment of structure activity relationship (SAR) clearly revealed that presence of less polar and more hydrophobic substituents positively favours the antibacterial activity, conversely, more polar and hydrophilic substituents favours the antifungal activities. Thus, the results positively endorsed the compounds as potent antibacterial and antifungal agents which could be developed as possible drug regimens.

Combining EQ-5D-5L items into a level summary score: demonstrating feasibility using non-parametric item response theory using an international dataset

BackgroundThe EQ-5D-5L is a well-established health questionnaire that estimates health utilities by applying preference-based weights. Limited work has been done to examine alternative scoring approaches when utility weights are unavailable or inapplicable. We examined whether the Mokken scaling approach can elucidate 1) if the level summary score is appropriate for the EQ-5D-5L and 2) an interpretation of such a score.MethodsThe R package “mokken” was used to assess monotonicity (scaling coefficients H, automated item selection procedure) and manifest invariant item ordering (MIIO: paired item response functions [IRF], HT). We used a rich dataset (the Multiple Instrument Comparison, MIC) which includes EQ-5D-5L data from six Western countries.ResultsWhile all EQ-5D-5L items demonstrated monotonicity, the anxiety/depression (AD) item had weak scalability (Hi = 0.377). Without AD, scalability improved from Hs = 0.559 to Hs = 0.714. MIIO revealed that the 5 items can be ordered, and the ordering is moderately accurate in the MIC data (HT = 0.463). Excluding AD, HT improves to 0.743. Results were largely consistent across disease and country subgroups.DiscussionThe 5 items of the EQ-5D-5L form a moderate to strong Mokken scale, enabling persons to be ordered using the level summary score. Item ordering suggests that the lower range of the score represents mainly problems with pain and anxiety/depression, the mid-range indicates additional problems with mobility and usual activities, and middle to higher range of scores reveals additional limitations with self-care. Scalability and item ordering are even stronger when the anxiety/depression item is not included in the scale.

Intra- and inter-laboratory comparison of mDixon and FastFung broths for Malassezia antifungal susceptibility testing.

Malassezia spp. antifungal susceptibility testing (AFST) capacities are limited by the lack of efficient and standardised AFST procedure, mainly because of the fastidious cultivation of these yeast. This study aimed to compare the FastFung broth (FFB) to modified Dixon broth (mDIXB) for the in vitro AFST of Malassezia spp. Fluconazole, ketoconazole, voriconazole and terbinafine MICs against a 19 Malassezia strains, including 6M furfur, 4M pachydermatis, 5M sympodialis and 4M slooffiae. The essential agreement (EA) between the two assays, and the intra- and inter-laboratory agreement of each assay were assessed. The MIC data obtained in our study were comparable to those reported in the literature. FFB showed to enhance Malassezia growth and displayed 100% (±2-fold dilution) EAs demonstrating similar performances to mDIXB. In addition, the MIC data obtained by using the FFB were reproducible between laboratories with EAs ranging from 94.7% to 100%. Therefore, FFB is a suitable alternative to mDXB for Malassezia spp. AFST.

Pharmacokinetic evaluation of cefquinome in febrile goats following intravenous administration

Pharmacokinetics of cefquinome was studied in febrile female goats following its intravenous (IV) administration at the dose rate of 2 mg/kg body weight. The fever was induced by administration of Escherichia coli lipopolysaccharide (lμg/kg body weight). Cefquinome concentration in plasma of goats was estimated using HPLC. The drug was detected upto 24 h in febrile goats. The disposition kinetics of the drug was described by twocompartment open model. PK-PD indices; AUC24h/MIC, Cmax/MIC, T>MIC were calculated by integrating in-vivo PK data with earlier generated MIC data against Pasteurella (P.) multocida. A favourable PK and PK-PD indices suggested that the dose of 2 mg/kg/24 h of cefquinome would be effective clinically to treat goats affected with P. multocida infections.

733. Ibrexafungerp Demonstrates Potent and Consistent In Vitro Activity Against >400 Global Candida auris Isolates, Including isolates with Elevated MIC’s to Echinocandins

Background Candida auris is an urgent global threat; a pathogen associated with high mortality (up to 60%), multi-drug resistance, the ability to spread from person-to-person and surface-to-person, presenting high risk for outbreaks in healthcare facilities. Echinocandins are the first-line treatment for patients with Candida auris infections given the high degree of resistance to azoles and polyenes. Ibrexafungerp is a novel IV/oral glucan synthase inhibitor (triterpenoid) antifungal with activity against Candida, Aspergillus and Pneumocystis spp, in Phase 3 development. We will present a compilation of >400 Candida auris isolates from four studies, including 32 Candida auris isolates with elevated MIC’s to the echinocandins.Methods In vitro MIC data for ibrexafungerp against Candida auris isolates were compiled from across 4 independent studies with the majority of isolates originating in the US and India. In vitro susceptibility was determined by broth micro-dilution using CLSI (M27-S3) and/or EUCAST methods. Overall, 445 isolates were evaluated including 32 isolates with elevated MIC values to one or more echinocandins.ResultsThe ibrexafungerp MIC90 value against the 445 clinical isolates was 1 μg/mL; the modal and MIC50 values were 0.5 μg/mL each. These results were consistent across the four studies and no differences were observed between MIC results generated using CLSI or EUCAST methods. Similar results were obtained for the 32 isolates with elevated MIC values to one or more of the echinocandins. Among this population, the mode, MIC50 and MIC90 were 0.5, 0.5, and 1 μg/mL, respectively. Only 1/32 of the echinocandin-resistant isolates had reduced sensitivity to ibrexafungerp (defined as > 2-dilutions vs the mode). This isolate was pan-resistant with elevated MICs to all three echinocandins (MICs = 4 μg/mL) as well as fluconazole (MIC >256 μg/mL) and amphotericin B (MIC = 1 μg/mL).ConclusionThis data demonstrates that ibrexafungerp possesses potent and consistent in vitro activity against Candida auris and remains highly active against C. auris isolates with high MIC’s to the echinocandins.DisclosuresKatyna Borroto-Esoda, PhD, SCYNEXIS, Inc. (Employee, Shareholder) David A. Angulo, MD, SCYNEXIS, Inc. (Employee, Shareholder) Nkechi Azie, MD, SCYNEXIS, Inc. (Employee, Shareholder)

Cumulative Fraction of Response for Once- and Twice-Daily Delamanid in Patients with Pulmonary Multidrug-Resistant Tuberculosis.

Pharmacokinetic (PK) and pharmacodynamic (PD) analyses were conducted to determine the cumulative fraction of response (CFR) for 100 mg twice-daily (BID) and 200 mg once-daily (QD) delamanid in patients with multidrug-resistant tuberculosis (MDR-TB), using a pharmacodynamic target (PDT) that achieves 80% of maximum efficacy. First, in the mouse model of chronic TB, the PK/PD index for delamanid efficacy was determined to be area under the drug concentration-time curve over 24 h divided by MIC (AUC0-24/MIC), with a PDT of 252. Second, in the hollow-fiber system model of tuberculosis, plasma-equivalent PDTs were identified as an AUC0-24/MIC of 195 in log-phase bacteria and 201 in pH 5.8 cultures. Third, delamanid plasma AUC0-24/MIC and sputum bacterial decline data from two early bactericidal activity trials identified a clinical PDT of AUC0-24/MIC of 171. Finally, the CFRs for the currently approved 100-mg BID dose were determined to be above 95% in two MDR-TB clinical trials. The CFR for the 200-mg QD dose, evaluated in a trial in which delamanid was administered as 100 mg BID for 8 weeks plus 200 mg QD for 18 weeks, was 89.3% based on the mouse PDT and >90% on the other PDTs. QTcF (QTc interval corrected for heart rate by Fridericia's formula) prolongation was approximately 50% lower for the 200 mg QD dose than the 100 mg BID dose. In conclusion, while CFRs of 100 mg BID and 200 mg QD delamanid were close to or above 90% in patients with MDR-TB, more-convenient once-daily dosing of delamanid is feasible and likely to have less effect on QTcF prolongation.

Pharmacokinetic profile of a single dose of an oral pradofloxacin suspension administered to eastern long-necked turtles (Chelodina longicollis).

The pharmacokinetics of fluoroquinolones in chelonians are well described but this does not extend to pradofloxacin, a broad-spectrum veterinary fluoroquinolone available as an oral suspension for cats and dogs. The aim of this study was to investigate the single-dose pharmacokinetic profile of pradofloxacin oral suspension at 7.5mg/kg in eastern long-necked turtles (Chelodina longicollis). Eight treated turtles were sampled at multiple time points up to 168hr. Plasma concentrations were measured using high-performance liquid chromatography. Pradofloxacin was quantifiable for up to 48hr after drug administration. The Tmax (9.0hr) and T½ to 48hr (13.16hr) were longer, and the Cmax (0.2μg/ml) and AUC0-24 (2.2hr*μg/ml) lower, than previously reported in cats and dogs. Pradofloxacin was measurable in tank water samples for up to 48hr. No adverse effects were observed in six turtles administered 7.5mg/kg sid for 7days. Using mammalian MIC data, the AUC0-24 /MIC ratios for a range of bacterial isolates suggest that this dose of pradofloxacin in turtles is unlikely to be effective against many bacterial pathogens.

Employing MIC Data for Mink Pathogens to Propose Tentative Epidemiological Cut-Off Values: A Step Toward Rationalizing Antimicrobial Use in Mink.

Optimizing antimicrobial dosage regimens and development of breakpoints for antimicrobial susceptibility testing are important prerequisites for rational antimicrobial use. The objectives of the study were (1) to produce MIC data for four mink pathogens and (2) to employ these MIC data to support the development of tentative epidemiological cut-off values (TECOFFs), which may be used for future development of mink-specific antimicrobial dosages and breakpoints. Broth microdilution was used to establish MIC distributions for 322 mink bacterial isolates of clinical origin from six European mink-producing countries. The included species were E. coli (n = 162), S. delphini (n = 63), S. canis (n = 42), and P. aeruginosa (n = 55). Sixty-four E. coli isolates and 34 S. delphini isolates were whole-genome sequenced and analyzed for antimicrobial resistance genes. No EUCAST MIC data are available on S. delphini and S. canis, hence tentative ECOFFs were suggested for the majority of the tested antimicrobials. For E. coli and P. aeruginosa, the wildtype distributions were in accordance with EUCAST data. Overall, the genotypes of the sequenced isolates were in concordance with the phenotypes. These data constitute an important piece in the puzzle of developing antimicrobial dosages and clinical breakpoints for mink. Until pharmacokinetic and clinical data become available, the (tentative) ECOFFs can be used for monitoring resistance development and as surrogates for clinical breakpoints.

Scaffold Modifications in Erythromycin Macrolide Antibiotics. A Chemical Minireview.

Clarithromycin and congeners are important antibacterial members of the erythromycin A 14-membered macrocyclic lactone family. The macrolide scaffold consists of a multifunctional core that carries both chemically reactive and non-reactive substituents and sites. Two main approaches are used in the preparation of the macrolides. In semisynthesis, the naturally occurring macrocycle serves as a substrate for structural modifications of peripheral substituents. This review is focused on substituents in non-activated positions. In the total synthesis approach, the macrolide antibiotics are constructed by a convergent assembly of building blocks from presynthesized substrates or substrates prepared by biogenetic engineering. The assembled block structures are linear chains that are cyclized by macrolactonization or by metal-promoted cross-coupling reactions to afford the 14-membered macrolactone. Pendant glycoside residues are introduced by stereoselective glycosylation with a donor complex. When available, a short summary of antibacterial MIC data is included in the presentations of the structural modifications discussed.

Optimal Dose or Optimal Exposure? Consideration for Linezolid in Tuberculosis Treatment

Exploring different ways of minimizing linezolid toxicity without compromising efficacy is a major quest in the treatment of drug-resistant tuberculosis (TB). The recently published study by Diacon et al. (1) indicates superior early bactericidal activity (EBA) from an intensive linezolid regimen (1,200 mg daily); however, this dosage has been associated with significant toxicity (2). Given the importance of optimal dose titration, the EBA of linezolid remains to be better characterized in relation to the area under the concentration-time curve (AUC0–24)/MIC ratio, which is the optimal pharmacokinetic/pharmacodynamic (PK/PD) marker of efficacy from hollow fiber system model (2, 3). The authors’ current analysis of EBA refers only to dose category, which is a crude measure of drug exposure. Clinical validation of the current efficacy and resistance suppression target of an AUC0–24/MIC of >100 (2, 3) is also needed from studies like that by Diacon et al. (1). Since in clinical practice, the MIC data are often unavailable during the early phase of the treatment, dose selection could be guided by AUC0–24/MIC thresholds based on the “critical concentration” of linezolid (1 mg/liter) for Mycobacterium tuberculosis (4).

Antimicrobial effect of ZnO nanoparticles synthesized by different methods against food borne pathogens and phytopathogens

Phytopathogens and food-borne pathogens are a major threat to human health, so there is an urgent need to find some alternatives to overcome these issues. Nanomaterials have shown great potential as antimicrobials therefore, in this study, ZnO nanoparticles were synthesized using Azadirachta indica leaf extract and studied for their antimicrobial activity. Their antimicrobial efficacy was studied against phyto and food borne pathogens and compared with the commercially available chemically synthesized ZnO nanoparticles (Chem-ZnO-NPs). The Azadirachta indica synthesized ZnO-NPs were characterized using UV–VIS spectroscopy, DLS, and FTIR. DLS data depicts that the size of nanoparticles in colloidal solution is approximately 96 nm, with polydispersity index (PDI) of 0.37. The antimicrobial activity was studied using pour plate method. The MIC data for food borne pathogens (E. coli and S. aureus) shows that Azadirachta indica mediated ZnO-NP are more efficient as compared to Chem-ZnO-NPs. For phytopathogens (Alternaria alternata, Sclerotium rolfsii and Stemphylium solani) also the result shows that Azadirachta indica mediated ZnO-NP exhibit more efficient antifungal properties. Therefore, the synthesized ZnO-NP can be efficiently used in place of commercially available fungal pesticides.

In Vitro Activity of Eravacycline against Gram-Negative Bacilli Isolated in Clinical Laboratories Worldwide from 2013 to 2017.

Eravacycline is a novel, fully synthetic fluorocycline antibiotic developed for the treatment of serious infections, including those caused by multidrug-resistant (MDR) pathogens. Here, we evaluated the in vitro activities of eravacycline and comparator antimicrobial agents against a global collection of frequently encountered clinical isolates of Gram-negative bacilli. The CLSI broth microdilution method was used to determine MIC data for isolates of Enterobacterales (n = 13,983), Acinetobacter baumannii (n = 2,097), Pseudomonas aeruginosa (n = 1,647), and Stenotrophomonas maltophilia (n = 1,210) isolated primarily from respiratory, intra-abdominal, and urinary specimens by clinical laboratories in 36 countries from 2013 to 2017. Susceptibilities were interpreted using both CLSI and EUCAST breakpoints. Multidrug-resistant (MDR) isolates were defined by resistance to agents from ≥3 different antimicrobial classes. The MIC90s ranged from 0.25 to 1 μg/ml for Enterobacteriaceae and were 1 μg/ml for A. baumannii and 2 μg/ml for S. maltophilia, Proteus mirabilis, and Serratia marcescens Eravacycline's potency was up to 4-fold greater than that of tigecycline against genera/species of Enterobacterales, A. baumannii, and S. maltophilia The MIC90s for five of six individual genera/species of Enterobacterales and A. baumannii were within 2-fold of the MIC90s for their respective subsets of MDR isolates, while the MDR subpopulation of Klebsiella spp. demonstrated 4-fold higher MIC90s. Eravacycline demonstrated potent in vitro activity against the majority of clinical isolates of Gram-negative bacilli, including MDR isolates, collected over a 5-year period. This study further underscores the potential benefit of eravacycline in the treatment of infections caused by MDR Gram-negative pathogens.

MIC distributions for amphotericin B, fluconazole, itraconazole, voriconazole, flucytosine and anidulafungin and 35 uncommon pathogenic yeast species from the UK determined using the CLSI broth microdilution method.

Epidemiological cut-off values and clinical interpretive breakpoints have been developed for a number of antifungal agents with the most common Candida species that account for the majority of infections due to pathogenic yeasts species. However, less-common species, for which susceptibility data are limited, are increasingly reported in high-risk patients and breakthrough infections. The UK National Mycology Reference Laboratory performs routine antifungal susceptibility testing of clinical yeast isolates submitted from across the UK. Between 2002 and 2016, >32 000 isolates representing 94 different yeast species were referred to the laboratory. Here we present antifungal susceptibility profiles generated over this period for amphotericin B, fluconazole, voriconazole, itraconazole, anidulafungin and flucytosine against 35 species of uncommon yeast using CLSI methodologies. MIC data were interpreted against epidemiological cut-off values and clinical breakpoints developed with Candida albicans, in order to identify species with unusually skewed MIC distributions that potentially indicate resistance. Potential resistance to at least one antifungal agent (>10% of isolates with MICs greater than the epidemiological cut-off or clinical breakpoint) was evidenced for 29/35 species examined here. Four species exhibited elevated MICs with all of the triazole antifungal drugs against which they were tested, and 21 species exhibited antifungal resistance to agents from at least two different classes of antifungal agent. This study highlights a number of yeast species with unusual MIC distributions and provides data to aid clinicians in deciding which antifungal regimens may be appropriate when confronted with infections with rarer yeasts.

Structural and Biological Properties of a Silver and Cobalt Complexes of Sulfamethazine in Presence of Secondary Ligand: An Experimental and Computational Approach

Silver and cobalt complexes of SMZ ligand [SMZ = 4-amino-N-(4, 6-dimethyl-2 pyrimidinyl) benzenesulfonamide] have been synthesized and characterized by elemental and FT-IR spectroscopy analysis. Due to the magnetic behaviour of the cobalt complex, it was characterized by EPR and magnetic susceptibility analysis. Single crystal X-ray diffraction study reveals the [Ag2(C12H14N4O2S)2(C6H7N)2], complex-1 crystallizes in orthorhombic space group Pbca, while [{Co(C12H13N4O2S)2(C5H5N)2}.(C5H5N)], complex-2 crystallizes in monoclinic space group C2/c. X-ray diffraction analysis revealed that silver in complex-1 is four-coordinate exhibiting distorted tetrahedral geometry, while cobalt in complex-2 is coordinated to six nitrogens leading to distorted octahedral geometry. The molecular structures of the complexes are stabilized by π…π and C–H…π intermolecular interactions. Furthermore, the computational studies such as frontier molecular orbital (FMO), natural bond orbital (NBO) and Mulliken population analysis (MPA) have been measured using DFT/B3LYP method in gaseous phase of the complexes. The visualized and correlated in a novel way through qualitative investigation using Hirshfeld surface and 3D energy frameworks analysis have been performed of the complexes. Additionally, The MIC data against a panel of gram positive and gram negative organisms suggest that both the complexes possess enhanced inhibitory activities than that of free SMZ ligand. Molecular docking investigation specifies that the binding affinity of the complexes with 1BNA is higher than that of free SMZ ligand.

"CLipP"ing on lipids to generate antibacterial lipopeptides.

We herein report the synthesis and biological and computational evaluation of 12 linear analogues of the cyclic lipopeptide battacin, enabled by Cysteine Lipidation on a Peptide or Amino Acid (CLipPA) technology. Several of the novel “CLipP”ed lipopeptides exhibited low micromolar MICs and MBCs against both Gram-negative and Gram-positive bacteria. The mechanism of action was then simulated with the MIC data using computational methods.

Does Dietary Consumption of Antibiotics by Humans Promote Antibiotic Resistance in the Gut Microbiome?

Mandated authorities have developed principles for evaluating the safety of antimicrobial residues in food and have established microbiological acceptable daily intakes (ADIs) and recommended maximum residue limits (MRLs) for antibiotic residues in food products. The evaluation of the ADI is based in relevant scientific information such as MIC data of predominant human intestinal bacteria. However, it does not include data derived from minimal selective concentration (MSC) predictions that estimate the lowest concentration of an antibiotic that will provide resistant bacteria an advantage over susceptible bacteria. Based on these insights, we sought to determine whether human exposure to selected antibiotics through ingestion of foodstuffs could result in colon concentrations exceeding apparent MSCs. Nine antibiotics-tetracycline, oxytetracycline, ciprofloxacin, sarafloxacin, erythromycin, spiramycin, tilmicosin, tylosin, and lincomycin-were selected for analysis. Dietary exposure was estimated either using published measured antibiotic concentrations in foodstuffs or using ADI values or food MRLs and a conservative diet. Using the ADI, the estimated antibiotic residue concentrations in the human colon of all antibiotics assessed may be up to a 1,000-fold greater than the predicted MSCs. When the dietary exposure assessment used MRLs or measured concentration in foodstuffs, the estimated concentrations were considerably lower but still within the MSC range for most of the foodstuffs assessed. These results suggest that the ingestion of antibiotic residues through food consumption may expose intestinal microbiota to antibiotic concentrations exceeding the MSC boundaries, thus favoring the growth of potential resistant bacteria. We suggest that MRL and ADI values be revisited in light of the recognition that antibiotic concentrations significantly below the MIC may select for resistance.

A pharmacokinetic-pharmacodynamic assessment of oral antibiotics for pyelonephritis

Antibiotic resistance to oral antibiotics recommended for pyelonephritis is increasing. The objective was to determine if there is a pharmacological basis to consider alternative treatments/novel dosing regimens for the oral treatment of pyelonephritis. A systematic review identified pharmacokinetic models of suitable quality for a selection of antibiotics with activity against Escherichia coli. MIC data was obtained for a population of E. coli isolates derived from patients with pyelonephritis. Pharmacokinetic/pharmacodynamic (PK/PD) simulations determined probability of target attainment (PTA) and cumulative fraction response (CFR) values for sub-populations of the E. coli population at varying doses. There are limited high-quality models available for the agents investigated. Pharmacokinetic models of sufficient quality for simulation were identified for amoxicillin, amoxicillin-clavulanic acid, cephalexin, ciprofloxacin, and fosfomycin trometamol. These antibiotics were predicted to have PTAs ≥ 0.85 at or below standard doses for the tested E. coli population including cephalexin 1500 mg 8 hourly for 22% of the population (MIC ≤ 4 mg/L) and ciprofloxacin 100 mg 12 hourly for 71% of the population (MIC ≤ 0.06 mg/L). For EUCAST-susceptible E. coli isolates, doses achieving CFRs ≥ 0.9 included amoxicillin 2500 mg 8 hourly, cephalexin 4000 mg 6 hourly, ciprofloxacin 200 mg 12 hourly, and 3000 mg of fosfomycin 24 hourly. Limitations in the PK data support carrying out additional PK studies in populations of interest. Oral antibiotics including amoxicillin, amoxicillin-clavulanic acid, and cephalexin have potential to be effective for a proportion of patients with pyelonephritis. Ciprofloxacin may be effective at lower doses than currently prescribed.

Regional analysis of telavancin and comparator antimicrobial activity against multidrug-resistant Staphylococcus aureus collected in the USA 2014-2016.

The in vitro antimicrobial activities of telavancin and comparator antimicrobials were evaluated against recent Staphylococcus aureus (S. aureus) clinical isolates collected in the United States of America (USA). A total of 15882 S. aureus isolates were collected (2014-2016) as part of the SENTRY Antimicrobial Surveillance Program from sites located in all US Census Bureau divisions. Broth microdilution MIC values were measured using current reference methods. Data were stratified by year and census division, and resistance rates were analysed for significant trends. Previously published data on methicillin-resistant S. aureus (MRSA) and multidrug-resistant (MDR) MRSA isolates (collected 2011-2013) were merged with the current isolate set to examine longer term resistance trends. Telavancin antimicrobial activity against MRSA and MDR MRSA isolates (MIC50/90 values, 0.03/0.06μg/mL for both subsets) remained unchanged over the 3-year surveillance period, and all isolates were susceptible to telavancin. No difference in telavancin activity was noted when MIC data were stratified by year or US Census Bureau division. When merged data (2011-2016) were analysed, the MRSA rate decreased for the entire USA and six individual census divisions, although the overall rate remained considerable. The overall US MDR MRSA rate also remained considerable and was unchanged from 2011-2016. The sustained potent activity of telavancin against US S. aureus isolates (100% susceptible) and the high rates of MRSA and MDR MRSA in the USA support the continued use of telavancin to treat indicated serious infections caused by S. aureus.