Minimum Inhibitory Concentration Distributions Research Articles

Unraveling Antimicrobial Resistance Dynamics in Mycoplasma gallisepticum: Insights Into Antibiotic and Disinfectant Interactions.

A major risk to the poultry industry is antimicrobial resistance (AMR), specifically with regard to Mycoplasma gallisepticum (MG) infections. The sensitivity patterns of 100 MG isolates to biocides and antibiotics were examined in this study to clarify the interactions between antimicrobial agents and resistance mechanisms. The antimicrobial activity against MG was assessed using broth microdilution, and the results are shown as the minimum inhibitory concentration (MIC) for each strain, the MIC distribution (range), the MIC50, and/or the MIC90. The statistical associations between the MICs of the antibiotics and biocides were investigated using regression model analysis and correlation coefficients. The absence of a cell wall in MG inherently confers resistance to beta-lactams, thereby necessitating the utilization of enrofloxacin, difloxacin, flumequine, oxytetracycline, chlortetracycline, doxycycline, tylosin, tilmicosin, tylvalosin, erythromycin, spiramycin, tiamulin, lincomycin, spectinomycin and dihydrostreptomycin. These antibiotics exhibited MIC50 values of 0.5, 0.5, 0.12, 0.062, 0.12, 0.031, 0.016, 0.016, 0.062, 16, 1, 0.008, 2, 0.5 and 32, respectively. In addition to antibiotics, disinfectants have garnered attention for their contribution to the development of AMR in MG. Notably, formalin, phenol, NADES, Halamid, Virkon-S, MicroSet and SteriSet exhibited MIC50 values of 125, 500, 31.25, 15.63, 15.63, 7.81 and 62.5, respectively. Significant positive correlations and direct associations were identified between various biocides and the development of antibiotic resistance, with coefficients ranging from 0.098 to 1.176. This research highlights the intricate nature of resistance profiles in MG and underscores the necessity for a thorough understanding of antimicrobial interactions. This finding emphasizes the importance of managing emerging AMR stemming from disinfectant misuse in the poultry farms to prevent additional constraints on antibiotic treatment options.

Imipenem pharmacokinetics/pharmacodynamics in preclinical hollow fiber model, dose-finding in virtual patients, and clinical evidence of efficacy for Mycobacterium abscessus lung disease.

Guideline-based therapy (GBT) for Mycobacterium abscessus (Mab) lung disease achieves sputum culture conversion rates (SCC) of 35%. This poor GBT efficacy is mirrored in the hollow fiber system model of Mab (HFS-Mab). While imipenem is part of GBT, biological effect with or without β-lactamase inhibitors, is unproven. We performed imipenem/relebactam minimum inhibitory concentration (MIC) in 122 Mab isolates, and an exposure-response study in the HFS-Mab using human intrapulmonary pharmacokinetics. The % time that concentration persisted above MIC (TMIC) mediating maximal effect in the HFS-Mab was used as the exposure target in 10,000 virtual subjects Monte Carlo experiment (MCE)-based dose-finding. For real-world evidence, we performed a patient, intervention (imipenem), comparison (no β-lactam), and outcome (SCC) (PICO) analysis. Imipenem killed 1.32 log10 CFU/mL below day 0 in HFS-Mab. Imipenem target exposure was TMIC=47.9±9.77%. 1g infusion, every 6h, achieved the target in >90% of virtual patients in MCEs. The pharmacokinetics/pharmacodynamics MIC breakpoint was 1mg/L. In PICO analyses, median days-to-SCC were 470 in comparators, 311 for imipenem added on failing regimen, and 37 in newly treated (p=0.049). The odds ratio for SCC when imipenem was part of the initial regimen versus comparators was 12.5 (95% confidence interval: 1.47 to 84.55). Patients on imipenem experienced no treatment-limiting adverse event, while 2/7 comparators did (p=0.0457). Middlebrook 7H9 broth MIC distribution, read at 24 hours, correlated better with patient responses than cation-adjusted Mueller Hinton broth. Imipenem demonstrated biologic effect in the HFS-Mab and in patients. Imipenem/relebactam doses of 1g every 6h are recommended.

Durlobactam to boost the clinical utility of standard of care β-lactams against Mycobacterium abscessus lung disease.

β-Lactams present several desirable pharmacodynamic features leading to the rapid eradication of many bacterial pathogens. Imipenem (IPM) and cefoxitin (FOX) are injectable β-lactams recommended during the intensive treatment phase of pulmonary infections caused by Mycobacterium abscessus (Mab). However, their potency against Mab is many-fold lower than against Gram-positive and Gram-negative pathogens for which they were optimized, putting into question their clinical utility. Here, we show that adding the recently approved durlobactam-sulbactam (DUR-SUL) pair to either IPM or FOX achieves growth inhibition, bactericidal, and cytolytic activity at concentrations that are within those achieved in patients and below the clinical breakpoints established for each agent. Synergies between DUR-SUL and IPM or FOX were confirmed across a large panel of clinical isolates. Through in vitro resistant mutant selection, we also show that adding DUR-SUL abrogates acquired resistance to IPM and FOX. Since the use of β-lactam injectables is firmly grounded in clinical practice during the intensive treatment phase of Mab pulmonary disease, their potentiation by FDA-approved DUR-SUL to bring minimum inhibitory concentration distributions within achievable concentration ranges could offer significant short-term benefits to patients, while novel β-lactam combinations are optimized specifically against Mab pulmonary infections, for which no reliable cure exists.

Prevalence and factors associated with human colonisation and vancomycin minimum inhibitory concentration of <em>Staphylococcus aureus</em> in Colombo, Sri Lanka

Introduction: Staphylococcus aureus is known to cause a wide variety of diseases of varying severity in humans. The objectives of this study were to determine the prevalence of S. aureus and methicillin resistant S. aureus (MRSA) colonisation, assess factors associated with MRSA colonisation, identify antibiotic susceptibility patterns of MRSA isolates, determine distribution of vancomycin minimum inhibitory concentrations (MIC) of S. aureus and factors associated with high vancomycin MIC values (≥2 µg/ml). Methods: A descriptive cross sectional study was conducted among 341 participants aged 18 to 84 years selected randomly from the Colombo district from 11th December 2018 to 10th April 2019. Samples were collected from the nose, axilla, groin of participants and identification and sensitivity testing of S. aureus were performed based on standard operation procedures given in the Laboratory manual in microbiology published by the Sri Lanka College of Microbiologists (2011). Results: Prevalence of S. aureus and MRSA colonisation in the sample population was 34.6% and 13.78% respectively. All MRSA isolates were susceptible to linezolid. MRSA susceptibility to gentamicin (86%), co-trimoxazole (88 %), and chloramphenicol (80%) was high. Erythromycin had the lowest susceptibility (20%). Inducible clindamycin resistance was demonstrated in 31% of isolates. Meat consumption and consumption of antibiotics within the previous six months showed a significant association with MRSA colonisation. Vancomycin MIC of S. aureus ranged from ≤ 0.5 to 2 µg/ml. Conclusion: As prevalence of MRSA colonisation is 13.78%, more attention should be paid when managing patients with suspected S. aureus infections presenting from the community. Further research on associated factors and environmental triggers are warranted with a larger sample size and different study design to formulate national regulations and guidelines.

Detection of multidrug-resistance in Mycobacterium tuberculosis by phenotype- and molecular-based assays

BackgroundThe whole-genome sequencing (WGS) is becoming an increasingly effective tool for rapid and accurate detection of drug resistance in Mycobacterium tuberculosis complex (MTBC). This approach, however, has still been poorly evaluated on strains from Central and Eastern European countries. The purpose of this study was to assess the performance of WGS against conventional drug susceptibility testing (DST) for the detection of multi-drug resistant (MDR) phenotypes among MTBC clinical strains from Poland and Lithuania.MethodsThe study included 208 MTBC strains (130 MDR; 78 drug susceptible), recovered from as many tuberculosis patients in Lithuania and Poland between 2018 and 2021. Resistance to rifampicin (RIF) and isoniazid (INH) was assessed by Critical Concentration (CC) and Minimum Inhibitory Concentration (MIC) DST as well as molecular-based techniques, including line-probe assay (LPA) and WGS. The analysis of WGS results was performed using bioinformatic pipeline- and software-based tools.ResultsThe results obtained with the CC DST were more congruent with those by LPA compared to pipeline-based WGS. Software-based tools showed excellent concordance with pipeline-based analysis in prediction of RIF/INH resistance. The RIF-resistant strains demonstrated a relatively homogenous MIC distribution with the mode at the highest tested MIC value. The most frequent RIF-resistance conferring mutation was rpoB S450L. The mode MIC for INH was two-fold higher among double katG and inhA mutants than among single katG mutants. The overall rate of discordant results between all methods was calculated at 5.3%. Three strains had discordant results by both genotypic methods (LPA and pipeline-based WGS), one strain by LPA only, three strains by MIC DST, two strains by both MIC DST and pipeline-based WGS, and the remaining two strains showed discordant results with all three methods, compared to CC DST.ConclusionsConsidering MIC DST results, current CCs of the first-line anti-TB drugs might be inappropriately high and may need to be revised. Both molecular methods demonstrated 100% specificity, while pipeline-based WGS had slightly lower sensitivity for RIF and INH than LPA, compared to CC DST.

Epidemiological cutoff values and genetic antimicrobial resistance of Lactococcus garvieae and L. petauri

Lactococcus garvieae and L. petauri are etiological agents of lactococcosis, which cause significant losses in trout aquaculture at elevated water temperatures. Optimizing antimicrobial dosage regimens and identifying the minimum inhibitory concentration (MIC) are important prerequisites for determining clinical breakpoints and effective antimicrobial use. In the present study, epidemiological cutoff values (ECV) were established for 14 antimicrobials using L. garvieae (n = 32) and L. petauri (n = 78), isolated from rainbow trout farms in Türkiye, Spain, Italy, and Greece. The provisional ECVs were calculated using the ECOFFinder and normalized resistance interpretation (NRI) approaches. Furthermore, gene cassettes, capsule gene clusters, and the presence of fourteen antibiotic resistance genes (ARGs) that encode resistance against seven antimicrobial agents, were evaluated. The calculated ECVs of antimicrobials ranged from 1.25 μg mL−1 for amoxicillin to 80.25 μg mL−1 for streptomycin. The percentages of wild type (WT) and non-wild type (NWT) isolates differed based on the approach, and ECVs calculated based on ECOFFinder approach were generally higher. Among the ARGs, those encoding resistance against tetracycline (tetA), β-lactamase (blaSHV, blaTEM, and blaOXA), amphenicol (floR), and macrolide (ermA) were detected in <10% of the isolates. The genes encoding resistance against quinolones (gyrA and qnrA) and aminoglycosides (strB) were the most detected genes. While 40.9% of the isolates contained Class 1 integron cassette regions, 33.6% of the isolates contained Class 2 integron cassette regions, and 9.1% of the isolates contained both cassette regions. None of the screened isolates were positive for the capsule gene cluster. Significant but weak correlations were found among and between ARGs and MIC distribution of antibiotics. The results of this study could be useful for identifying WT and non-WT isolates, as well as for susceptibility surveillance.

Minimum inhibitory concentrations of aztreonam-avibactam, ceftazidime-avibactam and meropenem in clinical isolates of Klebsiella pneumoniae harboring carbapenemase genes.

This study was aimed at understanding the distributions of the MICs (minimum inhibitory concentrations) of aztreonam-avibactam, ceftazidime-avibactam and meropenem with respect to Klebsiella pneumoniae isolates producing different types of carbapenemases and their combinations. K. pneumoniae isolates were collected between 2019 and 2022 from 37 hospitals. PCR was used to screen for blaKPC-, blaNDM- and blaOXA-48-like genes. MICs were determined by the broth microdilution method for meropenem, aztreonam-avibactam and ceftazidime-avibactam at a constant avibactam concentration of 4 mg l-1. MIC distributions were analyzed for groups of isolates based on the identified carbapenemases including their combinations. The AZT/AVI MIC50 and MIC90 for all NDM-positive isolates were 0.25 and 0.5, respectively, and for serine-carbapenemase-only producers, they were 0.25 and 1 mg l-1, respectively. The CZD/AVI MIC50 and MIC90 values for serine-carbapenemase-only producers were 1 and 4 mg l-1, respectively. The AZT/AVI MIC50 and MIC90 values for co-producers and single carbapenemase producers were the same (i.e., 0.25 and 1 mg l-1, respectively). The total proportion of meropenem-susceptible isolates (≤8 mg l-1) among all the carbapenemase producers was 25.1% (31.1% among single-carbapenemase producers and 9.2% among co-producers). The results support the use of aztreonam-avibactam for the empirical treatment of infections caused by any carbapenemase producers.

Optimizing Cefiderocol Dosing Through Population Pharmacokinetic/Pharmacodynamic Simulation: An Assessment of Drug Cost Reductions.

Cefiderocol is a siderophore cephalosporin antibiotic with bactericidal activity against carbapenem-resistant Enterobacterales. However, an efficient dosing strategy is yet to be developed. This study aimed to evaluate efficient lower-dose regimens and estimate potential drug cost reductions. This simulation study used a virtual population of 10,000 resampled individuals based on a reported population pharmacokinetic model. The target index for maximal bactericidal activity was the time for the unbound cefiderocol concentration to be above the minimum inhibitory concentration (TAM_unbound) of 100%, which was determined using a minimum inhibitory concentration distribution or specific value. The probability of achieving 100% TAM_unbound with the standard, low- (reduced by 1 g or one dose), and extended low- (reduced by 2 g or 2 doses) dose regimens was nearly 100%. The lowest probability of achieving 100% TAM_unbound with the extended low-dose regimen at a creatinine clearance range of 90-120 mL/min was 86.4%. The probability of achieving TAM_unbound of 100% was more than 90% for MIC of ≤0.5 mcg/mL with the extended low-dosing regimen. Furthermore, using an efficient dosing regimen reduced the medical costs over a 10-day treatment period for 10 patients, from $122,826.50 to $62,665.69 $ and ¥12,598,187 $ to ¥5,451,173 in the United States and Japan, respectively. A lower dosing regimen for cefiderocol could result in substantial reductions in drug costs while still achieving 100% TAM_unbound.

Application of Monte Carlo simulation to optimise the dosage regimen of meropenem in patients with augmented renal clearance for Pseudomonas aeruginosa infection

ObjectiveTo optimise the dosing regimen of meropenem for treating Pseudomonas aeruginosa (PA) infections in critically ill patients with augmented renal clearance (ARC) using pharmacokinetic/pharmacodynamic (PK/PD) principles and Monte Carlo simulation (MCS). MethodsThis research involves an MCS based on PK data from patients with ARC and a minimum inhibitory concentration (MIC) distribution of PA. This study simplifies the methods section, focusing on the critical aspects of simulation and target values for effective treatment. ResultsThe study highlights key findings and emphasises that tailored dosing based on bacterial MIC values is essential for patients with ARC. It also notes that empirical treatment in patients with ARC should consider the MIC distribution, with 2 g every (q) 6 h administered to achieve the PK/PD target, while 3 g q 6 h is effective in inhibiting resistance. ConclusionTailored dosing based on bacterial MIC values is crucial for patients with ARC. Prolonged infusion time alone does not enhance efficacy. Empirical treatment in patients with ARC should consider MIC distribution; a dosage of 2 g q 6 h achieves the PK/PD target, while 3 g q 6 h (≥12 g daily) inhibits resistance.

MIC distribution analysis identifies differences in AMR between population sub-groups.

Phenotypic data, such as the minimum inhibitory concentrations (MICs) of bacterial isolates from clinical samples, are widely available through routine surveillance. MIC distributions inform antibiotic dosing in clinical care by determining cutoffs to define isolates as susceptible or resistant. However, differences in MIC distributions between patient sub-populations could indicate strain variation and hence differences in transmission, infection, or selection. The Vivli AMR register contains a wealth of MIC and metadata for a vast range of bacteria-antibiotic combinations. Using a generalisable methodology followed by multivariate regression, we explored MIC distribution variations across 4 bacteria, covering 7,135,070 samples, by key population sub-groups such as age, sex and infection type, and over time. We found clear differences between MIC distributions across various patient sub-groups for a subset of bacteria-antibiotic pairings. For example, within Staphylococcus aureus, MIC distributions by age group and infection site displayed clear trends, especially for levofloxacin with higher resistance levels in older age groups (odds of 2.17 in those aged 85+ compared to 19-64), which appeared more often in men. This trend could reflect greater use of fluoroquinolones in adults than children but also reveals an increasing MIC level with age, suggesting either transmission differences or accumulation of resistance effects. We also observed high variations by WHO region, and over time, with the latter likely linked to changes in surveillance. We found that MIC distributions can be used to identify differences in AMR levels between population sub-groups. Our methodology could be used more widely to unveil hidden transmission sources and effects of antibiotic use in different patient sub-groups, highlighting opportunities to improve stewardship programmes and interventions, particularly at local scales.

Prevalence and genetic basis of Mycobacterium tuberculosis resistance to pretomanid in China

BackgroundPretomanid is a key component of new regimens for the treatment of drug-resistant tuberculosis (TB) which are being rolled out globally. However, there is limited information on the prevalence of pre-existing resistance to the drug.MethodsTo investigate pretomanid resistance rates in China and its underlying genetic basis, as well as to generate additional minimum inhibitory concentration (MIC) data for epidemiological cutoff (ECOFF)/breakpoint setting, we performed MIC determinations in the Mycobacterial Growth Indicator Tube™ (MGIT) system, followed by WGS analysis, on 475 Mycobacterium tuberculosis (MTB) isolated from Chinese TB patients between 2013 and 2020.ResultsWe observed a pretomanid MIC distribution with a 99% ECOFF equal to 0.5 mg/L. Of the 15 isolates with MIC values > 0.5 mg/L, one (MIC = 1 mg/L) was identified as MTB lineage 1 (L1), a genotype previously reported to be intrinsically less susceptible to pretomanid, two were borderline resistant (MIC = 2–4 mg/L) and the remaining 12 isolates were highly resistant (MIC ≥ 16 mg/L) to the drug. Five resistant isolates did not harbor mutations in the known pretomanid resistant genes.ConclusionsOur results further support a breakpoint of 0.5 mg/L for a non-L1 MTB population, which is characteristic of China. Further, our data point to an unexpected high (14/475, 3%) pre-existing pretomanid resistance rate in the country, as well as to the existence of yet-to-be-discovered pretomanid resistance genes.

Minimum inhibitory concentrations of azithromycin in clinical isolates of Mycobacterium avium complex in Japan.

The latest guidelines include azithromycin as a preferred regimen for treating Mycobacterium avium complex (MAC) pulmonary disease. However, serially collected susceptibility data on clinical MAC isolates are limited, and no breakpoints have been determined. We investigated the minimum inhibitory concentrations (MICs) of azithromycin and clarithromycin for all MAC strains isolated in 2021 from a single center in Japan, excluding duplicates. The MICs were determined using a panel based on the microbroth dilution method, according to the latest Clinical and Laboratory Standards Institute recommendations. The MICs were determined for 318 MAC strains. Although there was a significant positive correlation between the MICs of azithromycin and clarithromycin, the MICs of azithromycin tended to be higher than those of clarithromycin. Among the cases in which the strains were isolated, 18 patients initiated treatment, including azithromycin treatment, after sample collection. Some patients infected with stains with relatively high azithromycin MICs achieved a microbiological cure with azithromycin-containing regimens. This study revealed a higher MIC distribution for azithromycin than clarithromycin, raising questions about the current practice of estimating azithromycin susceptibility based on the clarithromycin susceptibility test result. However, this was a single-center study that included only a limited number of cases treated with azithromycin. Therefore, further multicenter studies that include a greater number of cases treated with azithromycin are warranted to verify the distribution of azithromycin MICs and examine the correlation between azithromycin MICs and treatment effectiveness.IMPORTANCEThe macrolides serve as key drugs in the treatment of pulmonary Mycobacterium avium complex infection, and the administration of macrolide should be guided by susceptibility test results. Azithromycin is recommended as a preferred choice among macrolides, surpassing clarithromycin; however, drug susceptibility testing is often not conducted, and clarithromycin susceptibility is used as a surrogate. This study represents the first investigation into the minimum inhibitory concentration of azithromycin on a scale of several hundred clinical isolates, revealing an overall tendency for higher minimum inhibitory concentrations compared with clarithromycin. The results raise questions about the appropriateness of using clarithromycin susceptibility test outcomes for determining the administration of azithromycin. This study highlights the need for future discussions on the clinical breakpoints of azithromycin, based on large-scale clinical research correlating azithromycin susceptibility with treatment outcomes.

Evaluation of omadacycline regimens for community-acquired bacterial pneumonia patients infected with Staphylococcus Aureus by pharmacokinetic/pharmacodynamic analysis

Omadacycline is an FDA-approved agent for community-acquired bacterial pneumonia (CABP). The purpose of this study is to evaluate the effectiveness of omadacycline for treating CABP patients infected with Staphylococcus aureus, including Methicillin-Resistant Staphylococcus aureus (MRSA) and Methicillin-Susceptible Staphylococcus aureus (MSSA), using pharmacokinetic/pharmacodynamic (PK/PD) analysis. Monte Carlo simulations (MCSs) were performed by utilizing omadacycline pharmacokinetic (PK) parameters, minimum inhibitory concentration (MIC) data, and in vivo PK/PD targets to calculate the probability of target attainment (PTA) and cumulative fraction of response (CFR) values for different dose regimens against MRSA and MSSA in CABP patients. A dosage regimen with a PTA or CFR expectation value greater than 90% was considered optimal. For all recommended dose regimens, PTA values for MRSA MIC ≤1 and MSSA MIC ≤4 on days 1, 4, and 7 were greater than 90%. Based on the MIC distribution of Staphylococcus aureus, all dose regimens had CFR values greater than 90% for both MRSA and MSSA. CFR values for different bacterial strains were still greater than 90% within the range of PK/PD target values less than 40, although they gradually decreased with increasing PK/PD target values. PK/PD modeling demonstrated that all recommended dose regimens of omadacycline are highly effective against CABP patients infected with MRSA and MSSA. The study provides theoretical support for the efficacy of omadacycline in different dose regimens.

The modern alchemy of clinical pathology: turning the output of microbiology laboratory operations into gold.

The clinical microbiology laboratory generates a huge amount of high-quality data that play a vital role in clinical care. With proper extraction, cleaning, analysis, and validation pipelines, these data can serve multiple other purposes that include supporting laboratory operations, understanding local epidemiology, informing hospital-specific policies, and public health surveillance. In this review, I use one of the core activities of the microbiology laboratory, antimicrobial susceptibility testing (AST), to illustrate several potential applications of next-generation data analytics. The first involves continuous monitoring of commercial AST systems using comparisons of minimum inhibitory concentration (MIC) distributions over time to trigger re-verification when statistically significant differences are detected. An extension of this is temporal analysis of joint MIC distributions to understand performance for multidrug-resistant organisms. More sophisticated analyses involve linking microbiologic data to clinical metadata to gain insight into the clinical validity of AST data and to inform treatment policies. The elements of a robust, validated analysis engine using routine data streams already exist, but numerous challenges must be overcome to make it a reality. Most importantly, it will require the sustained collaboration and advocacy of hospital leadership, microbiologists, clinicians, antimicrobial stewardship, data scientists, and regulatory agencies. Though no small feat, achieving this vision would provide an important resource for microbiology laboratories facing a rapidly evolving practice landscape and further cement its role as an integral part of a learning health system.

Integrative model-based comparison of target site-specific antimicrobial effects: A case study with ceftaroline and lefamulin

ObjectivePredictions of antimicrobial effects typically rely on plasma-based pharmacokinetic-pharmacodynamic (PK-PD) targets, ignoring target-site concentrations and potential differences in tissue penetration between antibiotics. In this study, we applied PK-PD modelling to compare target site-specific effects of antibiotics by integrating clinical microdialysis data, in vitro time-kill curves, and antimicrobial susceptibility distributions. As a case study, we compared the effect of lefamulin and ceftaroline against methicillin-resistant Staphylococcus aureus (MRSA) at soft-tissue concentrations. MethodsA population PK model describing lefamulin concentrations in plasma, subcutaneous adipose and muscle tissue was developed. For ceftaroline, a similar previously reported PK model was adopted. In vitro time-kill experiments were performed with six MRSA isolates and a PD model was developed to describe bacterial growth and antimicrobial effects. The clinical PK and in vitro PD models were linked to compare antimicrobial effects of ceftaroline and lefamulin at the different target sites. ResultsConsidering minimum inhibitory concentration (MIC) distributions and standard dosages, ceftaroline showed superior anti-MRSA effects compared to lefamulin both at plasma and soft-tissue concentrations. Looking at the individual antibiotics, lefamulin effects were highest at soft-tissue concentrations, while ceftaroline effects were highest at plasma concentrations, emphasising the importance of considering target-site PK-PD in antibiotic treatment optimisation. ConclusionGiven standard dosing regimens, ceftaroline appeared more effective than lefamulin against MRSA at soft-tissue concentrations. The PK-PD model-based approach applied in this study could be used to compare or explore the potential of antibiotics for specific indications or in populations with unique target-site PK.

Population pharmacokinetics of prophylactic cefoxitin in elective bariatric surgery patients: a prospective monocentric study

BackgroundThis study describes the population pharmacokinetics of cefoxitin in obese patients undergoing elective bariatric surgery and evaluates different dosing regimens for achievement of pre-defined target exposures. MethodsSerial blood samples were collected during surgery with relevant clinical data. Total serum cefoxitin concentrations were measured by chromatographic assay and analysed using a population PK approach with Pmetrics®. The cefoxitin unbound fraction (fu) was estimated. Dosing simulations were performed to ascertain the probability of target attainment (PTA) to achieve cefoxitin fu above minimum inhibitory concentrations (MIC) from surgical incision to wound closure. Fractional target attainment (FTA) was calculated against MIC distributions of common pathogens. ResultsA total of 123 obese patients (median BMI 44.3 kg/m2) were included with 381 cefoxitin concentration values. Cefoxitin was best described by a one-compartment model, with a mean clearance and volume of distribution of 10.9 ± 6.1 L/h and 23.4 ± 10.5 L, respectively. In surgery <2 h, a 2 and a 4 g doses were sufficient for an MIC up to 4 and 8 mg/L (fu 50%), respectively. In prolonged surgery (2–4 h), only continuous infusion enabled optimal PTA for an MIC up to 16 mg/L. Optimal FTAs were obtained against Staphylococcus aureus and Escherichia Coli only when simulating with 50% cefoxitin protein binding (intermittent regimen) and regardless of the protein binding for the continuous infusion. ConclusionIntermittent dosing regimens resulted in optimal FTAs against susceptible MIC distributions of S. aureus and E. coli when simulating with 50% cefoxitin protein binding. Continuous infusion of cefoxitin may improve FTA regardless of protein binding. Study registrationRegistration on ClinicalTrials.gov, NCT03306290

Longitudinal antimicrobial susceptibility trends of canine Staphylococcus pseudintermedius

Antimicrobial resistance within Staphylococcus pseudintermedius poses a significant risk for the treatment of canine pyoderma and as a reservoir for resistance and potential zoonoses, but few studies examine long-term temporal trends of resistance. This study assesses the antimicrobial resistance prevalence and minimum inhibitory concentration (MIC) trends in S. pseudintermedius (n=1804) isolated from canine skin samples at the Cornell University Animal Health Diagnostic Center (AHDC) between 2007 and 2020. Not susceptible (NS) prevalence, Cochran-Armitage tests, logrank tests, MIC50 and MIC90 quantiles, and survival analysis models were used to evaluate resistance prevalence and temporal trends to 23 antimicrobials. We use splines as predictors in accelerated failure time (AFT) models to model non-linear temporal trends in MICs. Multidrug resistance was common among isolates (47%), and isolates had moderate to high NS prevalence to the beta-lactams, chloramphenicol, the fluoroquinolones, gentamicin, the macrolides/lincosamides, the tetracyclines, and trimethoprim-sulfamethoxazole. However, low levels of NS to amikacin, rifampin, and vancomycin were observed. Around one third of isolates (38%) were found to be methicillin resistant S. pseudintermedius (MRSP), and these isolates had a higher prevalence of NS to all tested antimicrobials than methicillin susceptible isolates. Amongst the MRSP isolates, one phenotypically vancomycin resistant isolate (MIC >16 µg/mL) was identified, but genomic sequence data was unavailable. AFT models showed increasing MICs across time to the beta-lactams, chloramphenicol, the fluoroquinolones, gentamicin, and the macrolides/lincosamides, and decreasing temporal resistance (decreasing MICs) to doxycycline was observed amongst isolates. Notably, ATF modeling showed changes in MIC distributions that were not identified using Cochran-Armitage tests on prevalence, MIC quantiles, and logrank tests. Increasing resistance amongst these S. pseudintermedius isolates highlights the need for rational, empirical prescribing practices and increased antimicrobial resistance (AMR) surveillance to maintain the efficacy of current therapeutic agents. AFT models with non-linear predictors may be a useful, breakpoint-independent, surveillance tool alongside other modeling methods and antibiograms.

Challenges for global antibiotic regimen planning and establishing antimicrobial resistance targets: implications for the WHO Essential Medicines List and AWaRe antibiotic book dosing.

SUMMARYThe World Health Organisation's 2022 AWaRe Book provides guidance for the use of 39 antibiotics to treat 35 infections in primary healthcare and hospital facilities. We review the evidence underpinning suggested dosing regimens. Few (n = 18) population pharmacokinetic studies exist for key oral AWaRe antibiotics, largely conducted in homogenous and unrepresentative populations hindering robust estimates of drug exposures. Databases of minimum inhibitory concentration distributions are limited, especially for community pathogen-antibiotic combinations. Minimum inhibitory concentration data sources are not routinely reported and lack regional diversity and community representation. Of studies defining a pharmacodynamic target for ß-lactams (n = 80), 42 (52.5%) differed from traditionally accepted 30%-50% time above minimum inhibitory concentration targets. Heterogeneity in model systems and pharmacodynamic endpoints is common, and models generally use intravenous ß-lactams. One-size-fits-all pharmacodynamic targets are used for regimen planning despite complexity in drug-pathogen-disease combinations. We present solutions to enable the development of global evidence-based antibiotic dosing guidance that provides adequate treatment in the context of the increasing prevalence of antimicrobial resistance and, moreover, minimizes the emergence of resistance.

Minimum inhibitory concentrations of antifungals against invasive isolates of Cryptococcus species worldwide: Global antifungal antimicrobial testing leadership and surveillance program, 2010–2020

This study examined the geographic distribution of minimum inhibitory concentrations (MICs) of antifungals against Cryptococcus isolates. Data were collected on the MICs of specific antifungals (amphotericin B, 5-flucytosine, fluconazole, voriconazole, posaconazole, and isavuconazole) against various Cryptococcus species for the period 2010 to 2020 from the Antimicrobial Testing Leadership and Surveillance database. Cryptococcus isolates were collected from samples of blood and cerebrospinal fluid (CSF) from patients hospitalized in different regions worldwide. We applied the epidemiological cutoff values (ECVs) of antifungals against various Cryptococcus species to distinguish wild-type (WT) from non-WT Cryptococcus isolates. A total of 395 isolates of Cryptococcus species cultured from blood (n = 201) or CSF (n = 194) were analyzed. C. grubii (n = 270), C. neoformans (n = 111), and C. gattii (n = 11) were the three predominant species causing bloodstream infections (BSI) or meningitis/meningoencephalitis (MME). The proportion of MICs above the ECV (1 mg/L) for amphotericin B among C. neoformans isolates was significantly lower than that among C. gattii isolates (MICs >0.5 mg/L; P < 0.001), as evaluated using the chi-square test. For most isolates of the three predominant Cryptococcus species, the MICs of new triazoles were ≤0.25 mg/L. The MICs of fluconazole and amphotericin B in the BSI/MME-causing Cryptococcus isolates collected from patients hospitalized in the Asia-Western Pacific region and Europe were significantly lower (i.e., the distributions were more leftward) than those in North America and Latin America. Ongoing monitoring of MIC data for important antifungals against cryptococcosis is crucial.

Estimation of latamoxef (moxalactam) dosage regimens against β-lactamase-producing Enterobacterales in dogs: a pharmacokinetic and pharmacodynamic analysis using Monte Carlo simulation.

One of the most significant research areas in veterinary medicine is the search for carbapenem substitutes for the treatment of extended-spectrum β-lactamase (ESBL)-producing Enterobacterales (ESBL-E). This study applied a pharmacokinetic/pharmacodynamic (PK/PD) strategy in validating optimal latamoxef (LMX) therapeutic regimens against canine ESBL-E infections. Five dogs were administered a bolus dose of 40 mg/kg LMX intravenously to measure serum drug concentrations and determine PK indices using the noncompartmental model. The highest minimum inhibitory concentration (MIC) with a probability of target attainment ≥90% was used to compute the PK/PD cutoff values for bacteriostatic (time for which the unbound drug concentration was above the MIC [fTAM] ≥ 40%) and bactericidal (fTAM ≥ 70%) effects when administered at 20, 30, 50, and 60 mg/kg, in addition to 40 mg/kg. The cumulative fraction of response (CFR) was determined using the MIC distribution of wild-type ESBL-E in companion animals. The PK/PD cutoff values can be increased by reducing the dosing interval rather than increasing the dose per time. Based on the calculated CFRs for ESBL-producing Escherichia coli and Klebsiella pneumoniae, all LMX regimens in this study and those administered at 30-60 mg/kg every 8 and 6 hr were found to be optimal (CFR ≥ 90%) for exerting bacteriostatic and bactericidal effects, respectively. However, the regimens of 50 and 60 mg/kg every 6 hr may merely exert bacteriostatic effects on ESBL-producing Enterobacter cloacae. Further clinical trials are required to confirm the clinical efficacy of LMX.