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Biomedicine & Pharmacotherapy =... Jul 2023Therapeutic drug monitoring (TDM) for antibiotic drugs represents a consolidated practice to optimize the effectiveness and to limit the toxicity of specific drugs by...
BACKGROUND
Therapeutic drug monitoring (TDM) for antibiotic drugs represents a consolidated practice to optimize the effectiveness and to limit the toxicity of specific drugs by guiding dosage adjustments. The comparison of TDM results with drug-specific pharmacokinetic/pharmacodynamic (PK/PD) parameters, based on killing dynamics and bacterial susceptibility, increases the probability of therapeutic success.
PURPOSE
The aim of this study was the analytical validation of a new UHPLC-MS/MS assay for the quantification of 19 antibiotics divided in two different sets considering their chemical/pharmacological properties. This method has been implemented in an analytical LC-MS/MS Kit System by CoQua Lab s.r.l (Turin).
METHODS
The analytical validation is developed in accordance with "ICH Harmonized Guideline M10 on bioanalytical method validation and study sample analysis" and "Guidelines for regulatory auditing of quality management system of medical device manufacturers". Method suitability in the clinical context was tested by analysing clinical samples from patients treated with antibiotic drugs.
RESULTS
This method allows for simultaneous TDM of the following molecules: dalbavancin, daptomycin, linezolid, tedizolid, levofloxacin, moxifloxacin, meropenem, ertapenem, vaborbactam, avibactam, sulbactam, tazobactam, ceftazidime, ceftriaxone, ceftolozane, ceftobiprole, cefiderocol, ceftaroline and piperacillin. These drugs were quantified showing analytical performance parameters compliant with guidelines in terms of repeatability, reproducibility, robustness, bias, LOD, LOQ and linearity. The method was capable to successfully monitor drug concentrations in 65 samples from 52 patients undergoing treatment.
CONCLUSION
The UHPLC-MS/MS method described in this work can be useful for TDM of the reported antimicrobial agents. The analytical protocol is rapid and suitable to be used in routine analysis.
Topics: Humans; Anti-Bacterial Agents; Chromatography, Liquid; Tandem Mass Spectrometry; Chromatography, High Pressure Liquid; Reproducibility of Results
PubMed: 37126927
DOI: 10.1016/j.biopha.2023.114790 -
Antimicrobial Agents and Chemotherapy Aug 2023Recent clinical studies have reported additive nephrotoxicity with the combination of vancomycin and piperacillin-tazobactam. However, preclinical models have failed to...
Recent clinical studies have reported additive nephrotoxicity with the combination of vancomycin and piperacillin-tazobactam. However, preclinical models have failed to replicate this finding. This study assessed differences in iohexol-measured glomerular filtration rate (GFR) and urinary injury biomarkers among rats receiving this antibiotic combination. Male Sprague-Dawley rats received either intravenous vancomycin, intraperitoneal piperacillin-tazobactam, or both for 96 h. Iohexol-measured GFR was used to quantify real-time kidney function changes. Kidney injury was evaluated with the urinary biomarkers kidney injury molecule-1 (KIM-1), clusterin, and osteopontin. Compared to the control, rats that received vancomycin had numerically lower GFRs after drug dosing on day 3. Rats in this group also had elevations in urinary KIM-1 on experimental days 2 and 4. Increasing urinary KIM-1 was found to correlate with decreasing GFR on experimental days 1 and 3. Rats that received vancomycin plus piperacillin-tazobactam (vancomycin+piperacillin-tazobactam) did not exhibit worse kidney function or injury biomarkers than rats receiving vancomycin alone. The combination of vancomycin and piperacillin-tazobactam does not cause additive nephrotoxicity in a translational rat model. Future clinical studies investigating this antibiotic combination should employ more sensitive biomarkers of kidney function and injury, similar to those utilized in this study.
Topics: Male; Rats; Animals; Vancomycin; Iohexol; Piperacillin; Glomerular Filtration Rate; Penicillanic Acid; Retrospective Studies; Acute Kidney Injury; Drug Therapy, Combination; Rats, Sprague-Dawley; Anti-Bacterial Agents; Piperacillin, Tazobactam Drug Combination; Biomarkers
PubMed: 37428202
DOI: 10.1128/aac.00304-23 -
Anaesthesia, Critical Care & Pain... Dec 2023Broad-spectrum antibiotics such as beta-lactams and vancomycin are frequently used to treat critically ill patients, however, a significant number do not achieve target...
INTRODUCTION
Broad-spectrum antibiotics such as beta-lactams and vancomycin are frequently used to treat critically ill patients, however, a significant number do not achieve target exposures. Therapeutic drug monitoring (TDM) combined with Bayesian forecasting dosing software may improve target attainment in these patients. This study aims to describe the efficiency of dosing software for achieving target exposures of selected beta-lactam antibiotics and vancomycin in critically ill patients.
METHODS
A prospective cohort study was undertaken in an adult intensive care unit (ICU). Patients prescribed vancomycin, piperacillin-tazobactam and meropenem were included if they exhibited a subtherapeutic or supratherapeutic exposure informed by TDM. The dosing software, ID-ODS™, was used to generate dosing recommendations which could be either accepted or rejected by the treating team. Repeat antibiotic TDM were requested to determine if target exposures were achieved.
RESULTS
Between March 2020 and December 2021, 70 were included in the analysis. Software recommendations were accepted for 56 patients (80%) with 50 having repeated antibiotic measurements. Forty-three of the 50 patients (86%) achieved target exposures after one software recommendation, with 3 of the remaining 7 patients achieving target exposures after 2. Forty-seven patients out of the 50 patients (94%) achieved the secondary outcome of clinical cure. There were no antibiotic exposure-related adverse events reported.
CONCLUSION
The use of TDM combined with Bayesian forecasting dosing software increases the efficiency for achieving target antibiotic exposures in the ICU. Clinical trials comparing this approach with other dosing strategies are required to further validate these findings.
Topics: Adult; Humans; Anti-Bacterial Agents; Vancomycin; Prospective Studies; Critical Illness; Bayes Theorem; beta-Lactams; Software
PubMed: 37579945
DOI: 10.1016/j.accpm.2023.101296 -
JAC-antimicrobial Resistance Feb 2024Acute kidney injury (AKI) is a well-documented adverse effect observed with piperacillin/tazobactam in combination with vancomycin. The pharmacokinetics of these...
OBJECTIVES
Acute kidney injury (AKI) is a well-documented adverse effect observed with piperacillin/tazobactam in combination with vancomycin. The pharmacokinetics of these antibiotics when given in combination have not been previously evaluated. The purpose of this study was to compare the exposure of vancomycin + piperacillin/tazobactam in patients with and without AKI.
METHODS
Ninety adult patients, who received at least 72 h of vancomycin + piperacillin/tazobactam combination therapy and had available serum concentrations of vancomycin and piperacillin were included in the study. Nephrotoxicity was defined as a 1.5-fold increase in serum creatinine within 7 days from baseline. Median daily AUCs were calculated in those with nephrotoxicity (vancomycin + piperacillin/tazobactam 'N') versus those without nephrotoxicity (vancomycin + piperacillin/tazobactam 'WN') during the first 7 days of combination therapy.
RESULTS
The overall incidence of AKI in those receiving vancomycin + piperacillin/tazobactam was 20% (18/90). The median daily vancomycin AUCs did not differ between the vancomycin + piperacillin/tazobactam 'WN' and vancomycin + piperacillin/tazobactam 'N' groups. Although not statistically significant, the median daily vancomycin AUCs in the vancomycin + piperacillin/tazobactam 'N' group were numerically greater on Day 5 and trended downwards thereafter. For the piperacillin group, the median daily AUCs did not vary between groups, except on Day 7 where the vancomycin + piperacillin/tazobactam 'WN' group had statistically greater median piperacillin AUC than the vancomycin + piperacillin/tazobactam 'N' group ( = 0.046).
CONCLUSIONS
Utilizing serum creatinine-defined AKI, our study did not find any significant differences in vancomycin and piperacillin/tazobactam exposure between the groups with and without nephrotoxicity. These data indicate that vancomycin + piperacillin/tazobactam should not be avoided due to the risk of overexposure; instead, clinicians should continue to use these therapies cautiously.
PubMed: 38259903
DOI: 10.1093/jacamr/dlad157 -
The Journal of Infection Sep 2023Piperacillin-tazobactam resistance (P/T-R) is increasingly reported among Escherichia coli isolates. Although in vitro experiments have suggested that bla gene plays a...
Piperacillin-tazobactam resistance (P/T-R) is increasingly reported among Escherichia coli isolates. Although in vitro experiments have suggested that bla gene plays a key role in the P/T-R acquisition, no clinical in vivo study has yet confirmed the role of bla or other genes. Therefore, we aimed to identify the mechanisms underlying P/T-R by following up patients with E. coli complicated intra-abdominal infections (cIAI) who experienced P/T treatment failure. Four pairs of strains, clonally related from four patients, were isolated both before and after treatment with P/T dosed at 4 g/0.5 g intravenously. The P/T MIC was tested using broth microdilution, and β-lactamase activity was determined in these isolates. Whole-genome sequencing (WGS) was performed to decipher the role of bla and other genes associated with P/T-R. Changes in the outer membrane protein (OMP) profile were analyzed using SDS-PAGE, and bla and ompC transcription levels were measured by RT-qPCR. In addition, in vitro competition fitness was performed between each pairs of strains (P/T-susceptible vs. P/T-resistant). We found a higher copy number of bla gene in P/T-R isolates, generated by three different genetic events: (1) IS26-mediated duplication of the bla gene, (2) generation of a small multicopy plasmid (ColE-like) carrying bla, and (3) adaptive evolution via reduction of plasmid size, leading to a higher plasmid copy number. Moreover, two P/T-R strains showed reduced expression of OmpC. This study describes the mechanisms involved in the acquisition of P/T-R by E. coli in patients with cIAI. The understanding of P/T-R evolution is crucial for effectively treating infected patients and preventing the spread of resistant microorganisms.
Topics: Humans; Escherichia coli; Anti-Bacterial Agents; beta-Lactamases; Piperacillin, Tazobactam Drug Combination; Escherichia coli Infections; Intraabdominal Infections; Microbial Sensitivity Tests
PubMed: 37442373
DOI: 10.1016/j.jinf.2023.07.005 -
Cureus Oct 2023Recurrent adenotonsillitis (AT) commonly affects children and may be associated with various complications. Infections are common etiology, and microbial profiles may...
INTRODUCTION
Recurrent adenotonsillitis (AT) commonly affects children and may be associated with various complications. Infections are common etiology, and microbial profiles may vary widely in different cases. In this study, we evaluated the bacterial profile and antibiotic sensitivity of pathogens identified in tonsil and adenoid core cultures in children with recurrent AT.
METHODS
In this cross-sectional, observational study, culture and antibiotic sensitivity were performed from tonsil and adenoid core samples obtained after adenotonsillectomy of children (5 to 18 years) with recurrent AT. Children who had received antibiotics within one week before surgery were excluded. Drug sensitivity was performed only for drugs available on the hospital panel list.
RESULTS
Bacterial growth was observed in 83 (91.2%) tonsil core cultures (n=91) and 43 (79.6%) adenoid core cultures (n=54). In the tonsil and adenoid core cultures, poly-microbial growth was seen in 25 (27.0%) and 11 (25.6%) children, respectively. From the tonsil core cultures, the majority of the bacteria were sensitive to ciprofloxacin, ampicillin, piperacillin-tazobactam, cefoperazone-sulbactam, ceftazidime, cefotaxime, levofloxacin. From the adenoid core culture, the majority of the bacteria were sensitive to ciprofloxacin, ampicillin, piperacillin-tazobactam, cefoperazone-sulbactam, cephalexin, and cefotaxime.
CONCLUSION
In recurrent AT, polymicrobial growth is not uncommon in both tonsil and adenoid core cultures. Identifying the correct pathogens and their antibiotic sensitivity patterns can help plan treatment strategies for the effective management of recurrent AT.
PubMed: 38022121
DOI: 10.7759/cureus.47650 -
Transplantation and Cellular Therapy Oct 2023Acute kidney injury (AKI) is one of the major complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The use of multiple antimicrobials is...
Acute kidney injury (AKI) is one of the major complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The use of multiple antimicrobials is one of the major causes of post-transplantation AKI, owing to the potential nephrotoxicity of each agent and of drug-drug interactions (DDIs). No satisfactory reports on DDIs the field of allo-HSCT have been published. We performed a retrospective analysis to compare the incidence of AKI within 100 days post-transplantation. A total of 465 allo-HSCTs in 416 patients were analyzed, and the cumulative incidence of AKI was 40.0%. AKI was associated with significantly reduced overall survival (hazard ratio [HR], 2.66; 95% confidence interval [CI] 1.95 to 3.55; P < .01) and increased transplantation-related mortality (HR, 4.77, 95% CI, 2.90 to 7.88; P < .01). A higher incidence of AKI was significantly associated with the use of ciprofloxacin, cefepime, tazobactam/piperacillin, meropenem, vancomycin, liposomal amphotericin B, ganciclovir, and foscarnet. Among these drugs, combinations of vancomycin plus tazobactam/piperacillin (HR, 2.23; P = .09 for interaction), ganciclovir plus cefepime (HR, 5.93; P = .04), and ganciclovir plus meropenem (HR, 2.63; P = .12) synergistically increased the risk of AKI, whereas combinations involving teicoplanin did not. This is the first report dealing with DDIs after allo-HSCT, indicating that such combinations should be avoided to preserve renal function and reduce AKI-related morbidity and mortality.
PubMed: 37481244
DOI: 10.1016/j.jtct.2023.07.017 -
Antimicrobial Agents and Chemotherapy Nov 2023Recently, several β-lactam (BL)/β-lactamase inhibitor (BLI) combinations have entered clinical testing or have been marketed for use, but limited direct comparative...
potency of xeruborbactam in combination with multiple β-lactam antibiotics in comparison with other β-lactam/β-lactamase inhibitor (BLI) combinations against carbapenem-resistant and extended-spectrum β-lactamase-producing .
Recently, several β-lactam (BL)/β-lactamase inhibitor (BLI) combinations have entered clinical testing or have been marketed for use, but limited direct comparative studies of their activity exist. Xeruborbactam (XER, also known as QPX7728), which is undergoing clinical development, is a cyclic boronate BLI with potent inhibitory activity against serine (serine β-lactamase) and metallo-β-lactamases (MBLs). The objectives of this study were (i) to compare the potency and spectrum of β-lactamase inhibition by various BLIs in biochemical assays using purified β-lactamases and in microbiological assays using the panel of laboratory strains expressing diverse serine and metallo-β-lactamases and (ii) to compare the potency of XER in combination with multiple β-lactam antibiotics to that of other BL/BLI combinations in head-to-head testing against recent isolates of carbapenem-resistant (CRE). Minimal inhibitory concentrations (MICs) of XER combinations were tested with XER at fixed 4 or 8 µg/mL, and MIC testing was conducted in a blinded fashion using Clinical and Laboratory Standards Institute reference methods. Xeruborbactam and taniborbactam (TAN) were the only BLIs that inhibited clinically important MBLs. The spectrum of activity of xeruborbactam included several MBLs identified in e.g., and various IMP enzymes and NDM-9 that were not inhibited by taniborbactam. Xeruborbactam potency against the majority of purified β-lactamases was the highest in comparison with other BLIs. Meropenem-xeruborbactam (MEM-XER, fixed 8 µg/mL) was the most potent combination against MBL-negative CRE with MIC values of 0.125 µg/mL. MEM-XER and cefepime-taniborbactam (FEP-TAN) were the only BL/BLIs with activity against MBL-producing CREs; with MEM-XER (MIC of 1 µg/mL) being at least 16-fold more potent than FEP-TAN (MIC of 16 µg/mL). MEM-XER MIC values were ≤8 µg/mL for >90% of CRE, including both MBL-negative and MBL-positive isolates, with FEP-TAN MIC of >8 µg/mL. Xeruborbactam also significantly enhanced potency of other β-lactam antibiotics, including cefepime, ceftolozane, ceftriaxone, aztreonam, piperacillin, and ertapenem, against clinical isolates of that carried various class A, class C, and class D extended-spectrum β-lactamases and carbapenem-resistant , including metallo-β-lactamase-producing isolates. These results strongly support further clinical development of xeruborbactam combinations.
Topics: beta-Lactamase Inhibitors; Anti-Bacterial Agents; Carbapenems; beta Lactam Antibiotics; Cefepime; Lactams; beta-Lactamases; Serine; Microbial Sensitivity Tests; Azabicyclo Compounds
PubMed: 37800963
DOI: 10.1128/aac.00440-23 -
Medicina (Kaunas, Lithuania) Sep 2023. Numerous studies have been conducted to explore the epidemiological characteristics of urinary tract infections (UTI) and sepsis. However, there is still a lack of...
. Numerous studies have been conducted to explore the epidemiological characteristics of urinary tract infections (UTI) and sepsis. However, there is still a lack of relevant bacteriological features and prognostic information regarding urosepsis based on bacteriological etiology. The current study aims to evaluate the bacterial etiology of complicated UTI (cUTI) and bacterial resistance to antibiotics and whether they present an intrinsic risk of developing urosepsis. . A retrospective study was performed that included 102 patients who were diagnosed with cUTI and admitted to the urology department of the "Sfântul Apostol Andrei" County Emergency Clinical Hospital (GCH) from September 2019 to May 2022. A considerable number of patients, n = 41 (40.2%), were diagnosed with multi drug-resistant (MDR) infection. () was identified as the prevailing pathogen, accounting for 51 patients. manifested itself as the subsequent causative agent in 27 instances. The presence of spp. infection was documented in 13 patients, whereas emerged as the etiological perpetrator in the clinical context of 8 patients. The current study found a substantial prevalence of resistance to first-line antibiotics. The overall resistance rate was 74.5% for penicillin, 58.82% for trimethoprim-sulfamethoxazole and 49% for fluoroquinolones; cephalosporin resistance displayed an inverse correlation with antibiotic generation with fourth-generation cephalosporins exhibiting a resistance rate of 24.5%, and first-generation cephalosporins demonstrating a resistance rate of 35.29%. . Age, comorbidities and indwelling urinary catheters are risk factors for developing MDR infections. While the intrinsic characteristics of the causative bacterial agent in cUTI may not be a risk factor for developing urosepsis, they can contribute to increased mortality risk. For empiric antibiotic treatment in patients with cUTI who are at a high risk of developing urosepsis and experiencing a potentially unfavorable clinical course, broad-spectrum antibiotic therapy is recommended. This may include antibiotics, such as amikacin, tigecycline, carbapenems and piperacillin-tazobactam.
Topics: Humans; Escherichia coli; Retrospective Studies; Anti-Bacterial Agents; Urinary Tract Infections; Bacteria; Bacterial Infections; Cephalosporins
PubMed: 37763805
DOI: 10.3390/medicina59091686 -
JAC-antimicrobial Resistance Feb 2024(Hi) is a Gram-negative bacterium that may cause sepsis or meningitis, treatment of which mainly includes β-lactam antibiotics. Since 2019 EUCAST breakpoints for...
BACKGROUND
(Hi) is a Gram-negative bacterium that may cause sepsis or meningitis, treatment of which mainly includes β-lactam antibiotics. Since 2019 EUCAST breakpoints for piperacillin/tazobactam have been available. Little is known about the prevalence and mechanisms of piperacillin/tazobactam resistance in Hi.
OBJECTIVES
To provide reliable prevalence data for piperacillin/tazobactam resistance in Hi in Germany, to evaluate different antibiotic susceptibility testing methods and to examine possible resistance mechanisms.
METHODS
According to EUCAST breakpoints, the MIC for piperacillin/tazobactam resistance is >0.25 mg/L. All invasive Hi in Germany from 2019 were examined by gradient agar diffusion (GAD) for piperacillin/tazobactam susceptibility. Piperacillin/tazobactam broth microdilution (BMD), piperacillin GAD on tazobactam-containing agar [piperacillin GAD on Mueller-Hinton agar with horse blood (MH-F)/tazobactam) and piperacillin/tazobactam agar dilution (AD) were used for confirmation. Phenotypic testing was complemented by sequencing.
RESULTS
Piperacillin/tazobactam GAD resulted in 2.9% (21/726) resistant Hi. BMD did not confirm piperacillin/tazobactam resistance. Two strains were found resistant by AD, of which one was also resistant using piperacillin GAD on MH-F/tazobactam. Overall, we found two strains with a piperacillin/tazobactam MIC >0.25 mg/L in at least two different tests (0.3%). Both were β-lactamase-producing amoxicillin/clavulanate-resistant with PBP3 mutations characterized as group III-like+. Relevant PBP3 mutations occurred in six strains without phenotypic piperacillin/tazobactam resistance. These mutations suggest a reduced efficacy of β-lactam antibiotics in these isolates.
CONCLUSIONS
Piperacillin/tazobactam resistance prevalence in invasive Hi is low in Germany. Reduced susceptibility was correlated with PBP3 mutations, in particular with group III mutations.
PubMed: 38161964
DOI: 10.1093/jacamr/dlad148