High MICs Research Articles

PKPD modelling and simulation of longitudinal meropenem in vivo effects against Escherichia coli and Klebsiella pneumoniae strains with high MIC

PKPD modelling and simulation of longitudinal meropenem in vivo effects against Escherichia coli and Klebsiella pneumoniae strains with high MIC

Clinical and microbiological characteristics of Eggerthella lenta causing bacteremia

Eggerthella lenta is an obligate anaerobic, Gram-positive bacilli, belonging to the human microbiota of gastrointestinal and female reproductive tracts, oral cavity and prostate gland. In this article, we aim to describe clinical and microbiological characteristics of seven E. lenta strains causing bacteremia. We conducted a descriptive retrospective study including all E. lenta strains causing bacteremia, from February 2019 to August 2023 at the Basurto University Hospital. Seven patients were included in the study with a mean age of 72.7 years. Six patients presented risk factors associated with bacterial infections. All patients were admitted to the hospital because of suspicious of bloodstream infection associated with abdominal symptoms for intravenous antibiotic treatment. Four E. lenta isolates were resistant to penicillin, while all isolates presented high MICs to piperacillin/tazobactam and low MICs to amoxicillin/clavulanic acid. All patients recovered without no complications.

Genomic epidemiology and resistant genes of Acinetobacter baumannii clinical strains in Vietnamese hospitals.

Introduction. Acinetobacter baumannii is a common cause of multidrug-resistant (MDR) nosocomial infections worldwide, including Vietnam.Hypothesis. Analysis of crucial genetic factors may link to epidemiological characteristics and antibiotic resistance of A. baumannii clinical strains in Vietnamese hospitals.Methodology. Fifty-one A. baumannii clinical strains from six different tertiary hospitals in Vietnam were analysed using whole genome sequencing (WGS), between 2017 and 2019.Results. Eleven sequence types (STs) were identified, including four STs reported for the first time in Vietnam based on the PubMLST database and three new STs not previously documented. ST1336, ST1260 and ST575 were found exclusively in Vietnam. These STs were widely distributed in all hospitals in Vietnam, with ST2 and ST571 being the most dominant. Resistant rates to eight antibiotics, belonging to four antibiotic groups, were very high (72.5-94.1 %) with high MIC values, while resistance to colistin was 29.4%. Fifty-one isolates were identified as MDR, with 100% (51/51) isolates carrying antimicrobial-resistant (AMR) genes, and 52 antibiotic-resistant genes were detected among these strains, including β-lactam (22 genes), chloramphenicol (5 genes), lincosamide (2 genes), aminoglycoside (11 genes), rifampicin (1 gene), quinolone (2 genes), sulfonamide and trimethoprim (4 genes) and tetracycline (5 genes) resistance. The most commonly found mobile structures carried partial or complete transposons: ISaba24/ISEc29/ISEc35 contains a series of antibiotic-resistant genes.Conclusion. The WGS results of the 51 strains of A. baumannii provided important information regarding the distribution of STs and associated antibiotic-resistant genes among A. baumannii strains.

Prevalence and genetic characterization of linezolid resistance gene reservoirs in hospital sewage from Zhejiang Province, China

Hospital sewage represented important hotspots for the aggregation and dissemination of clinically relevant pathogens and antimicrobial resistance genes. To investigate the prevalence and molecular epidemiology of linezolid resistance genes in hospital sewage, both influent and effluent samples from 11 hospitals in Zhejiang Province, China, were collected and analyzed for linezolid resistance gene carriers. Thirty colonies of putative isolates that grew on the selective media with 10 mg/L florfenicol were randomly picked per sample. A total of 420 Gram-positive isolates, including 330 from 11 influent samples and 90 from three effluent samples, were obtained. Each isolate carried at least one of the linezolid resistance genes, including optrA, poxtA, cfr, and cfr(D), and the optrA gene was highly dominant (388/420). Enterococci displayed predominance among the linezolid resistance gene carriers in the hospital sewage, exhibiting a resistance rate to linezolid of 77.8 %. The wild-type OptrA and OptrA variants KLDP, RDK, and KLDK, all associated with high linezolid MICs, were most frequently detected. Phylogenetic analysis revealed the multispecies and polyclonal distribution of linezolid-resistant bacteria in hospital sewage, while Enterococcus faecalis sequence types (STs) 16 and 179 demonstrated the widest dissemination across different hospitals. Despite generally high genetic diversity, phylogenetic analysis showed that 87 isolates, assigned to ten STs from both sewage and other sources, were genetically related. Moreover, the genetic environment of linezolid resistance genes in isolates from sewage was similar to that from animals, humans, or the environment, with “Tn554-fexA-optrA” as the most common structure. These findings revealed the potential risk of the transmission of linezolid resistance genes through hospital sewage to other environments.

Occurrence of antimicrobial resistance and class 1 integrons in Staphylococcus aureus isolated from bovine mastitis in China.

Integrons are important genetic elements that allow easy acquisition and dissemination of antimicrobial resistance genes. Studies reporting occurrence of integrons in Staphylococcus aureus (S. aureus) isolated from bovine mastitis in large dairy farms across China are scarce. The aim of this study was to investigate the occurrence of class 1 integrons (intI1), antimicrobial resistance (AMR) and associated genes in S. aureus isolated from bovine mastitis and their associations. Minimum inhibitory concentrations (MICs) were determined to evaluate the AMR phenotypes, whereas PCR was carried out to assess the occurrence of AMR genes and intI1. In addition, index cluster analysis was used to estimate associations between AMR phenotype, genotype and intI1 in 103 isolates. Overall, 83% of S. aureus were intI1-positive and 5 types of gene cassettes were detected. Susceptibility against single antimicrobial agents ranged from 0% (erythromycin), 12% (ampicillin) and 16% (penicillin G) to 96% (gentamicin). Most isolates (64%) were intermediate-resistant against erythromycin, whereas resistance against ceftriaxone (22%), clindamycin (4%), cefotaxime (2%), tetracycline (1%) and ciprofloxacin (1%) were relatively uncommon. The predominant resistant gene was blaZ gene (n = 88, 85%) followed by tetD gene (n = 85, 83%). With an estimated prevalence of 12% of the mecA gene, methicillin-resistant S. aureus isolates had higher MIC50 and MIC90 for majority of antimicrobials than methicillin-susceptible S. aureus isolates. Presence of the ermC gene was associated with erythromycin resistance. Ampicillin, erythromycin and penicillin G resistance were associated with intI1. The data presented in our study indicated that class 1 integron-mediated resistance possibly plays an important role in dissemination of AMR in S. aureus isolated from bovine mastitis.

Two novel plasmids harbouring the multiresistance gene cfr in porcine Staphylococcus equorum

BackgroundThe emergence and transmission of the multidrug resistance gene cfr have raised public health concerns worldwide. ObjectivesMultidrug-resistant Staphylococcus equorum isolates can pose a threat to public health. In this study, we have characterised the whole-genome of one Staphylococcus equorum isolate harbouring two distinct cfr-carrying plasmids. MethodsAntimicrobial susceptibility testing was performed by broth microdilution. Genomic DNA was sequenced using both the Illumina HiSeq X Ten and Nanopore MinION platforms. De novo hybrid assembly was performed by Unicycler. Genomic data were assessed by in silico prediction and bioinformatic tools. ResultsStaphylococcus equorum isolate SN42 exhibited resistance or high MICs to linezolid, erythromycin, tetracycline, oxacillin, clindamycin, virginiamycin, tiamulin, chloramphenicol and florfenicol. It carried two cfr-harbouring plasmids: the RepA N-family plasmid pSN42–51 K and the Inc18-family plasmid pSN42–50 K. These two plasmids exhibited low structural similarities to the so far reported cfr-carrying plasmids. Both plasmids harboured an arsenic resistance operon, copper and cadmium resistance genes as well as the lincosamide-pleuromutilin-streptogramin A resistance gene lsa(B). In addition, plasmid pSN42–51 K carried two erm(B) genes for macrolide-lincosamide-streptogramin B resistance, the streptomycin resistance gene ant(6)-Ia as well as mercury resistance genes while pSN42–50 K was associated with the heavy metal translocating P-type ATPase gene hmtp. The co-carriage and co-existence of these antimicrobial resistance and heavy metal resistance genes increases the likelihood of co-selection of the cfr-carrying plasmids. ConclusionThis is the first report of S. equorum carrying two distinct cfr-carrying plasmids, underscoring the need for ongoing surveillance to address the potential dissemination of multi-drug resistance in bacteria from food-producing animals to ensure food safety and public health.

Варианты генов Mycobacterium tuberculosis, ассоциированные с лекарственной устойчивостью к фторхинолонам (обзор литературы)

Background: The spread of M. tuberculosis drug resistance to fluoroquinolones poses a threat to their long-term clinical efficacy. Understanding the mechanisms of formation of drug resistance to fluoroquinolones, based on information on genes associated with drug resistance of M. tuberculosis, is important for optimizing TB chemotherapy regimens. The aim of the study: To study the available literature data on the most significant variants of M. tuberculosis genes associated with drug resistance to fluoroquinolones. Materials and methods: To achieve this goal, the task was to analyze the sources of domestic and foreign literature on this priority issue over the past 5 years. The databases of scientific electronic libraries PubMed, Elibriary were used. Results: Mycobacterial resistance to fluoroquinolones is associated with mutations in the gyrA and gyrB genes, encoding the GyrA and GyrB subunits of DNA gyrase, the main target of fluoroquinolones. In the fluoroquinolone-binding pocket of the “DNA-gyrase + DNA” catalytic center, the fluoroquinolone molecule is supported by the gyrA and gyrB regions, which determine resistance to fluoroquinolones (QRDR-A and QRDR-B). Modification of any of the constituent fragments of these regions affects the level of resistance to fluoroquinolones. Small quinolone molecules (nalidixic acid) have a high MIC against Mtb and other bacteria, while larger PC molecules (sparfloxacin, sitafloxacin, gatifloxacin, levofloxacin and moxifloxacin) are tightly adjacent to the fluoroquinolone-binding pocket and have a lower MIC. Modification of the DNA structure can change the spatial structure of the pocket itself, which leads to destabilization of the fluoroquinolone inside it. Thus, the presence of heteroresistance of the tuberculosis pathogen to fluoroquinolones indicates the active development of its resistance to this group of drugs in modern conditions. Conclusion: Analysis of modern studies shows the dependence of drug resistance of mycobacteria on fluoroquinolone compounds, while most often resistance to a decrease in the concentration of fluoroquinolones is associated with substitutions in the gyrB gene, as well as mutations in the gyrA gene. It has also been established that in addition to the main studied regions of the gyrA and gyrB genes associated with phenotypic drug resistance to fluoroquinols, there are regions that have not been sufficiently studied so far. These areas cannot be diagnosed in the clinical work of bacteriological laboratories of anti-tuberculosis institutions.

Antimicrobial and Antioxidant Activities of 18β-Glycyrrhetinic Acid Biotransformed by Aspergillus niger

The search for novel plant-based antioxidant and antibacterial medication has garnered a lot of attention lately. Glycyrrhiza glabra, known as licorice, is one of the most important medicinal plants. The primary component of Glycyrrhiza glabra is glycyrrhizin, which is biotransformed into 18α- and 18β-glycyrrhetinic acid for a variety of medicinal purposes. The goal of this study was to improve the bioavailability of glycyrrhizin by its biotransformation into glycyrrhetinic acid by Aspergillus niger. The biotransformation process was optimized using response surface methodology. A two-level Plackett–Burman design was employed to identify the factors that had a significant impact on the process of biotransformation. The three main variables were pH, glycerrhizin concentration, and incubation time. These three medium components were further optimized using a 3-level Box–Behnken design, and their optimum levels were pH of 8, an incubation period of 6 days, and a glycyrrhizin concentration of 1%. Using these optimum conditions, the maximum level obtained was 159% greater than in the screening experiment. Regarding the antimicrobial activity of glycyrrhizin extract, Bacillus subtilis emerged as the most sensitive organism with the lowest MIC (60 µg/mL) and the highest zone of inhibition (17 mm). The most resistant organism was Pseudomonas aeruginosa, which had the highest MIC (400 µg/mL) and the smallest zone of inhibition (10 mm). In the case of glycyrrhetinic acid, Bacillus subtilis was the most sensitive organism with the highest zone of inhibition (32 mm) and the lowest MIC (20 µg/mL). Pseudomonas aeruginosa was the most resistant organism, with the lowest zone of inhibition (18 mm), and the highest MIC (140 µg/mL). The antioxidant activity of glycyrrhizin extract increased from 12.81% at a concentration of 63 µg/100 µL to 41.41% at a concentration of 1000 µg/100 µL, while that of glycyrrhetinic acid extract increased from 35.5% at a concentration of 63 µg/100 µL to 76.85% at a concentration of 1000 µg/100 µL. The present study concluded that biotransformation of glycyrrhizin into glycyrrhetinic acid increased its bioavailability and antioxidant and antimicrobial activities. Glycyrrhizin and glycyrrhetinic acid might be used as a natural antimicrobial and antioxidant in pharmaceutical industries

Amikacin treatment in patients with Enterobacterales bacteraemia: impact of MIC on mortality.

Recently, breakpoints of Enterobacterales to amikacin were changed from MIC ≤ 16 mg/L to MIC ≤ 4 mg/L based mainly on laboratory data with little supporting clinical evidence. Our aim was to investigate the relation between MIC of Enterobacterales to amikacin and mortality among patients with Enterobacterales bacteraemia from a urinary tract source treated with amikacin. This retrospective, single-centre study included patients with Enterobacterales urinary source bacteraemia treated with amikacin, with Low (MIC ≤ 4 mg/L) and High (MIC 8 or 16 mg/L) MICs. A cohort of patients treated with ertapenem was used to assess if amikacin MIC is a marker of severity independent of antimicrobial treatment. The primary outcome was 30-day mortality. Multivariate logistic regression analysis was done to assess risk factors for mortality. We included 85 patients, 46 (54.1%) were male, and mean age was 79.0 years (SD 11.7). Sixty-one patients (71.8%) had Low MIC and 24 (28.2%) had High MIC. Thirty-day mortality was 8.2% and 29.2% in the Low and High MIC groups, respectively (P = 0.031). Risk factors for 30-day mortality were age, infection by Enterobacterales other than Escherichia coli and high amikacin MIC. In a cohort of 88 patients treated with ertapenem, amikacin MIC was not associated with 30-day mortality. We demonstrated a relation between higher amikacin MIC levels (8 and 16 mg/L) and increased 30-day mortality in patients treated with amikacin for bacteraemia secondary to a urinary source. These findings support the new CLSI breakpoint change of Enterobacterales to amikacin.

Understanding chromoblastomycosis in Sri Lanka; insights into fungal aetiology and antifungal susceptibility patterns

Introduction: Chromoblastomycosis is a chronic disfiguring fungal infection of the subcutaneous tissue found mainly in the socio-economically marginalized population in the tropical and sub-tropical regions, characterized by the presence of sclerotic cells. This study was done with the aim of identifying the antifungal sensitivity patterns of the causative agents of chromoblastomycosis in Sri Lanka from 1992 to 2019.Methodology: Study was done on the stored isolates received from patients with chromoblastomycosis since 1992 to 2019, to the Mycology Reference Laboratory of Medical Research Institute, Colombo. Isolates were revived by subculture on Potato dextrose agar. Identification was done phenotypically. Antifungal sensitivity testing was performed by E test method. Available demographic and clinical data were analysed.Results: Of the 74 isolates, 71 (96%) were caused by Fonsecaea pedrosoi. Mean MIC for the antifungals tested were lowest for posaconazole 0.015 μg/ml followed by itraconazole 0.225 μg/ml, and voriconazole 0.768 μg/ml while amphotericin B demonstrated complete resistance with mean MIC of 30.591 μg/ml. No statistically significant differences were noted on the antifungal sensitivity of the isolates from 1992 to 2004 and 2005 to 2019.Conclusions: Fonsecaea pedrosoi was the commonest causative agent causing chromoblastomycosis in the studied population. Posaconazole demonstrated the lowest MIC values for the tested isolates followed by itraconazole and voriconazole. Amphotericin B demonstrated very high MIC values which were likely to result in clinical failure upon treatment. MIC values demonstrated minimal fluctuations throughout the tested time.

Wild chamomile essential oils bioactivity at different locations in sulaimani region, Iraq

This study was conducted to evaluate the bioactivity of wild chamomile (Matricaria chamomile L.), in response to different elevations flower samples at full blooming. The analysis of chamomile flower essential oils (EOs) through GC-MS identified the predominant abundance of terpenoids including Bisabolol oxides, farnesene, and Azulen, constituting 61.765% of the identified compounds across various locations. The highest concentration was 74.554% out of the total components observed at Kanipanka, while it was the minimum (16.414%) at the Qaradagh location. Oppositely the highest concentration of Farnasene was observed at the Qaradagh location, while the lowest concentration occurred with the essential oil of Kanipanka.α-Bisabolol oxide A% dominates, except in the Qara Dagh location. The best antioxidant concentration was found in Sharbazher essential oil. The essential oil in Sharbazher significantly shows the highest inhibition capacity (IC%). The stronger IC50% value was 64.645 µg mL-1, recorded at the Qara Dagh location. The disc diffusion assay revealed that the activity of chamomile essential oil at various locations significantly affected the death of most bacterial strains (Gram-negative and Gram-positive). Chamomile EOs from the Kanipanka location recorded maximum antibacterial activity on Pseudomonas aeruginosaPenjween EOs observed the maximum antibacterial activity against Staphylococcus haemolyticus, while a high level inhibition zone (IZ) against Enterococcus faecalis was observed in Bakrajo. The finding revealed that the highest MIC and MBC against Pseudomonas aeruginosa were achieved with the concentration of 2.5 µg mL-1 of Kanipanka EOs.

Frequency of cefiderocol heteroresistance among patients treated with cefiderocol for carbapenem-resistant Acinetobacter baumannii infections.

Cefiderocol exhibits potent in vitro activity against carbapenem-resistant Acinetobacter baumannii (CRAb), but this activity has not consistently translated to improved outcomes among patients. Cefiderocol heteroresistance, or the presence of a resistant subpopulation, has been proposed as one possible explanation. The objective of this study was to explore associations between heteroresistance and outcomes of patients with CRAb infections. Baseline CRAb isolates were collected from 27 consecutive patients in the USA and Italy. Cefiderocol susceptibility was tested by broth microdilutions in triplicate. Heteroresistance was defined by population analysis profiling in duplicate. Resistance mechanisms and strain relatedness were evaluated through comparative genomic analysis. Overall, 59% of infecting CRAb isolates were identified as cefiderocol-heteroresistant; rates were higher among isolates from Italy (79%) than the USA (38%). The median Charlson Comorbidity and SOFA scores were 4 and 5, respectively; 44% of patients had pneumonia, which was the most common infection type. Rates of 28-day clinical success and survival were 30% and 73%, respectively. By broth microdilution, cefiderocol MICs ≥1 mg/L were associated with higher failure rates than MICs ≤0.5 mg/L (81% versus 55%). Rates of clinical failure were numerically higher among patients infected by cefiderocol-heteroresistant compared with susceptible CRAb (81% versus 55%). Whole-genome sequencing identified a premature stop codon in the TonB-dependent receptor gene piuA in six isolates, all of which were heteroresistant. This pilot study supports the hypothesis that cefiderocol treatment failure may be associated with higher MICs and/or the presence of heteroresistance. Further studies are needed to confirm these findings.

Agar dilution test and its Merits and Drawbacks in evolving dynamics of colistin susceptibility

ObjectivesAutomated results for determining colistin susceptibility tests are unreliable, micro broth dilution requires expertise, and CBDE has limited dilutions. International Consensus Document of 2022 suggested that agar dilution was unacceptable due to varying results in the literature. MethodsThe study was designed to evaluate the agar dilution method for colistin susceptibility in CRE isolates compared to CBDE. In the study, 108 carbapenem-resistant isolates were tested for Colistin susceptibility by Microbroth Dilution, agar dilution, and colistin broth disc elution. The comparisons were made using various statistical parameters. ResultsThe results of the agar dilution method revealed an essential agreement of 75 % and a categorical agreement of 92.5 %. The method showed a sensitivity of 75 % and a specificity of 97.7 %. The positive and negative predictive values were 88.2 % and 94.5 %, respectively. Youden's index was 0.727, indicating a moderate level of accuracy. Meanwhile, CBDE diagnostic accuracy tests were better, with Youden's index at 0.939. ConclusionsWhile CBDE demonstrated better accuracy parameters, it did not offer a broader MIC range. In contrast, agar dilution showed reasonable specificity and reliability for isolates with high MIC. Therefore, we propose using CBDE for screening and agar dilution as a supplementary test in the approach to colistin susceptibility.

Penicillin concentrations in oropharyngeal and frontal sinus tissue following enteral and intravenous administration measured by microdialysis in a porcine model

BackgroundPenicillin may be administered enterally or intravenously for the treatment of bacterial infections within the oropharynx and the frontal sinuses. We aimed to assess and compare penicillin concentrations in oropharyngeal and frontal sinus tissues following enteral and intravenous administration in a porcine model. MethodTwelve pigs were randomized to receive either enteral (0.8 g Penicillin V) or intravenous (1.2 g Penicillin G) penicillin. Microdialysis was used for sampling in oropharyngeal and frontal sinus tissues during a six-hour dosing interval. In addition, plasma samples were collected. The primary endpoints were time with drug concentration above the minimal inhibitory concentration (T>MIC) for two MIC targets: 0.125 (low target) and 0.5 (high target) μg/mL (covering Group A Streptococci, Fusobactarium necrophorum, Streptococcus pneumoniae and Hemophilus influenza) and attainment of these treatment targets for ≥50 % T>MIC. ResultsFor both the low and high MIC targets, intravenous administration resulted in higher T>MIC in oropharyngeal and frontal sinus tissues compared to enteral administration. In oropharyngeal tissue, the treatment target (≥50 % T>MIC) was achieved for both the low target (96 %) and high target (68 %) when penicillin was administrated intravenously. In frontal sinus tissue, the treatment target was reached for the low target (70 %), but not the high target (35 %) when administered intravenously. None of the two tissues reached the treatment targets when penicillin was administered enterally. ConclusionIntravenous administrated penicillin in standard dosage is superior to enteral administration of penicillin in standard dosage in achieving clinically important T>MIC as the majority of targets were achieved following intravenously administration, while none of the targets were achieved following enteral administration. These results support the general notion of higher tissue concentrations following intravenous compared to enteral administration.

In vitro Development of Two Alternaria solani Strains, Causal Agent of Alternariose in Tomato (Lycopersicon esculentum) under the Influence of Thevetia peruviana Seeds Extracts

Alternaria solani is a fungus that causes yield losses of up to 80 % in tomato production in field. Synthetic fungicides are the most widely used for its controbl, but have harmful consequences. The objective of this work was to test in vitro the antifungal potential of Thevetia peruviana seed extracts against two A. solani isolates. Aqueous, methanol, ethyl acetate and acetone extracts, at concentrations 12.5, 25, 50 and 100 µL/mL were used. Two synthetic fungicides Maneb (5.33 µg/mL) and Dimethomorph + Clorothalonil (3.75 µg/mL) and control (0 µL/mL) were also tested on two A. solani isolates (Mbal and Foum). The investigation was repeated three times. Phytochemical screening, mycelial growth, spore germination and minimum inhibitory concentrations (MIC50 and MIC90) were determined. The results showed that T. peruviana extracts are rich in many families of bioactive compounds such as alkaloids, phenolic compounds and sugars. All extracts tested show high inhibition of mycelial growth (100%) and spore germination (100%) of the two strains at highest concentration (100 µL/mL). Acetone extract at a concentration of 50 µL/mL inhibited mycelial growth by 88.45 and 86.55% and spore germination by 88.33 and 80.33%, respectively for the Mbal and Foum isolates. The lowest MIC50 (16.63 µL/mL) and MIC90 (54.6 µL/mL) were obtained with the acetone extract on the Mbal isolate while the highest MIC50 (27.5 µL/mL) and MIC90 (61.7 µL/mL) were observed with ethyl acetate on the Foum isolate These extracts can therefore be used in the biological control against Alternariose in tomato.

Dose optimization of cefazolin in South African children undergoing cardiac surgery with cardiopulmonary bypass.

Cefazolin is an antibiotic used to prevent surgical site infections. During cardiac surgery with cardiopulmonary bypass (CPB), its efficacy target could be underachieved. We aimed to develop a population pharmacokinetic model for cefazolin in children and optimize the prophylactic dosing regimen. Children under 25 kg undergoing cardiac surgery with CPB and receiving cefazolin at standard doses (50 mg/kg IV every 4-6 h) were included in this analysis. A population pharmacokinetic model and Monte Carlo simulations were used to evaluate the probability of target attainment (PTA) for efficacy and toxicity with the standard regimen and an alternative regimen of continuous infusion, where loading and maintenance doses were calculated from model-derived individual parameters. Twenty-two patients were included, with median (range) age, body weight, and eGFR of 19.5 (1-94) months, 8.7 (2-21) kg, and 116 (48-159) mL/min, respectively. Six patients received an additional dose in the CPB circuit. A two-compartment disposition model with an additional compartment for the CPB was developed, including weight-based allometric scaling and eGFR. For a 10 kg patient with eGFR of 120 mL/min/1.73 m2, clearance was estimated as 0.856 L/h. Simulations indicated that the standard dosing regimen fell short of achieving the efficacy target >40% of the time within a dosing duration and in patients with good renal function, PTA ranged from <20% to 70% for the smallest to the largest patients, respectively, at high MICs. In contrast, the alternative regimen consistently maintained target concentrations throughout the procedure for all patients while using a lower overall dose.

Molecular basis of the persistence of chloramphenicol resistance among Escherichia coli and Salmonella spp. from pigs, pork and humans in Thailand.

This study aimed to investigate the potential mechanisms associated with the persistence of chloramphenicol (CHP) resistance in Escherichia coli and Salmonella enterica isolated from pigs, pork, and humans in Thailand. The CHP-resistant E. coli (n = 106) and Salmonella (n = 57) isolates were tested for their CHP susceptibility in the presence and absence of phenylalanine arginine β-naphthylamide (PAβN). The potential co-selection of CHP resistance was investigated through conjugation experiments. Whole genome sequencing (WGS) was performed to analyze the E. coli (E329, E333, and E290) and Salmonella (SA448, SA461, and SA515) isolates with high CHP MIC (32-256 μg/mL) and predominant plasmid replicon types. The presence of PAβN significantly reduced the CHP MICs (≥4-fold) in most E. coli (67.9%) and Salmonella (64.9%). Ampicillin, tetracycline, and streptomycin co-selected for CHP-resistant Salmonella and E. coli-transconjugants carrying cmlA. IncF plasmids were mostly detected in cmlA carrying Salmonella (IncFIIAs) and E. coli (IncFIB and IncF) transconjugants. The WGS analysis revealed that class1 integrons with cmlA1 gene cassette flanked by IS26 and TnAs1 were located on IncX1 plasmid, IncFIA(HI1)/HI1B plasmids and IncFII/FIB plasmids. IncFIA(HI1)/HI1B/Q1in SA448 contained catA flanked by IS1B and TnAs3. In conclusion, cross resistance through proton motive force-dependent mechanisms and co-selection by other antimicrobial agents involved the persistence of CHP-resistance in E. coli in this collection. Dissemination of CHP-resistance genes was potentially facilitated by mobilization via mobile genetic elements.

505 Fusarium Isolates in Burn-injured Patients: Clinical Characteristics and Susceptibility Patterns

Abstract Introduction Fusarium species are ubiquitous in the environment and can cause opportunistic infections in burn-injured patients. Patients with larger burns, prolonged lengths of stay, concomitant antimicrobial use and invasive lines are at higher risk for Fusarium infections. Little data exists on clinical characteristics and in vivo antifungal susceptibilities in burn-injured patients. Methods All positive Fusarium species cultures were retrospectively identified between November 2017 to June 2023 at a regional burn center. Demographic, clinical and microbiologic susceptibility data was collected from the electronic medication record. Descriptive statistics were used to describe the cohort. Results A total of 18 patients had positive Fusarium wound cultures during the study period. The average age was 38.4 ± 11.9 years. The average %TBSA was 54.5 ± 23.4 % and R-Baux score of 92.9 ± 29.3. The most common mechanism of injury was thermal burn (17 patients, 94%). This cohort experienced prolonged ICU (68.9 ± 31.9 days) and hospital (73.6 ± 38.2 days) lengths of stay. The average time from burn injury to positive Fusarium cultures was 19.6 ± 9.0 days. Mechanical ventilation was prolonged (46.1 ± 23.3 days). The average central line duration prior to Fusarium infection was 9.8 ± 10.2 days. Susceptibility data was obtained for voriconazole in 15 patients and for amphotericin in 14 patients. For voriconazole, 5/15 tested isolates had an MIC of 4, 1/15 had an MIC of 8, and 9/15 (60%) isolates returned with MIC ≥ 16. A majority (13/14, 93%) of the MICs tested for amphotericin were ≤ 1. Patients were taken to the OR for source control in all cases. Ten of 18 patients with Fusarium positive infections survived to hospital discharge (55%). The most common cause of death was multi-system organ failure and sepsis (88%). Recorded adverse drug events possibly due to voriconazole and posaconazole included transaminitis (4 cases), QTc prolongation (1 case), and hallucinations (1 case). Amphotericin was suspected of contributing to an acute kidney injury in 1 case. Conclusions This case series reports the clinical characteristics and susceptibility data on Fusarium isolates in a burn-injured population. This cohort was critically ill based on the %TBSA, R-Baux score, and high rate of mechanical ventilation. The MIC results obtained for voriconazole demonstrated a majority of isolates with relatively high MIC values ≥ 16. A majority of the MICs for amphotericin were &amp;lt; 1. It is important to note that no established breakpoints exist for Fusarium species and clinical outcomes are dependent on a variety of factors beyond the susceptibility data. Applicability of Research to Practice Empiric double coverage with voriconazole and amphotericin or amphotericin monotherapy should be considered when Fusarium is a suspected primary pathogen.

45 years of tetracycline post exposure prophylaxis for STIs and the risk of tetracycline resistance: a systematic review and meta-analysis

There is considerable interest in the use of doxycycline post exposure prophylaxis (PEP) to reduce the incidence of bacterial sexually transmitted infections (STIs). An important concern is that this could select for tetracycline resistance in these STIs and other species. We searched PubMed and Google Scholar, (1948–2023) for randomized controlled trials comparing tetracycline PEP with non-tetracycline controls. The primary outcome was antimicrobial resistance (AMR) to tetracyclines in all bacterial species with available data. Our search yielded 140 studies, of which three met the inclusion criteria. Tetracycline PEP was associated with an increasedprevalence of tetracycline resistance in Neisseria gonorrhoeae, but this effect was not statistically significant (Pooled OR 2.3, 95% CI 0.9-3.4). PEP had a marked effect on the N. gonorrhoeae tetracycline MIC distribution in the one study where this was assessed. Prophylactic efficacy was 100% at low MICs and 0% at high MICs. In the one study where this was assessed, PEP resulted in a significant increase in tetracycline resistance in commensal Neisseria species compared to the control group (OR 2.9, 95% CI 1.5-5.5) but no significant effect on the prevalence of tetracycline resistance in Staphylococcus aureus. The available evidence suggests that PEP with tetracyclines could be associated with selecting tetracycline resistance in N. gonorrhoeae and commensal Neisseria species.

The yeast genus Tardiomyces gen. nov. with one new species and two new combinations

PurposeRare yeasts species are increasingly reported as causative agents of invasive human infection. Proper identification and antifungal therapy are essential to manage these infections. Candida blankii is one of these emerging pathogens and is known for its reduced susceptibility to multiple antifungals.MethodsTo obtain more insight into the characteristics of this species, 26 isolates reported as C. blankii were investigated using genetic and phenotypical approaches.ResultsAmong the 26 isolates, seven recovered either from blood, sputum, urine, or the oral cavity, displayed substantial genetic and some phenotypical differences compared to the other isolates, which were confirmed as C. blankii. We consider these seven strains to represent a novel species, Tardiomyces depauwii. Phylogenomics assigned C. blankii, C. digboiensis, and the novel species in a distinct branch within the order Dipodascales, for which the novel genus Tardiomyces is erected. The new combinations Tardiomyces blankii and Tardiomyces digboiensis are introduced. Differences with related, strictly environmental genera Sugiyamaella, Crinitomyces, and Diddensiella are enumerated. All three Tardiomyces species share the rare ability to grow up to 42 °C, display slower growth in nutrient-poor media, and show a reduced susceptibility to azoles and echinocandins. Characteristics of T. depauwii include high MIC values with voriconazole and a unique protein pattern.ConclusionWe propose the novel yeast species Tardiomyces depauwii and the transfer of C. blankii and C. digboiensis to the novel Tardiomyces genus.