The Neonatal and Paediatric Pharmacokinetics of Antimicrobials study (NAPPA): investigating amoxicillin, benzylpenicillin, flucloxacillin and piperacillin pharmacokinetics from birth to adolescence.

BACKGROUND: Pharmacokinetic (PK) data underlying paediatric penicillin dosing remain limited, especially in critical care. OBJECTIVES: The primary objective of the Neonatal and Paediatric Pharmacokinetics of Antimicrobials study (NAPPA) was to characterize PK profiles of commonly used penicillins using data obtained during routine care, to further understanding of PK variability and inform future evidence-based dosing. METHODS: NAPPA was a multicentre study of amoxicillin, co-amoxiclav, benzylpenicillin, flucloxacillin and piperacillin/tazobactam. Patients were recruited with informed consent. Antibiotic dosing followed standard of care. PK samples were obtained opportunistically or at optimal times, frozen and analysed using UPLC with tandem MS. Pharmacometric analysis was undertaken using NONMEM software (v7.3). Model-based simulations (n = 10 000) tested PTA with British National Formulary for Children (BNFC) and WHO dosing. The study had ethical approval. RESULTS: For the combined IV PK model, 963 PK samples from 370 participants were analysed simultaneously incorporating amoxicillin, benzylpenicillin, flucloxacillin and piperacillin data. BNFC high-dose regimen simulations gave these PTA results (median fT>MIC at breakpoints of specified pathogens): amoxicillin 100% (Streptococcus pneumoniae); benzylpenicillin 100% (Group B Streptococcus); flucloxacillin 48% (MSSA); and piperacillin 100% (Pseudomonas aeruginosa). Oral population PK models for flucloxacillin and amoxicillin enabled estimation of first-order absorption rate constants (1.16 h-1 and 1.3 h-1) and bioavailability terms (62.7% and 58.7%, respectively). CONCLUSIONS: NAPPA represents, to our knowledge, the largest prospective combined paediatric penicillin PK study undertaken to date, and the first paediatric flucloxacillin oral PK model. The PTA results provide evidence supportive of BNFC high-dose IV regimens for amoxicillin, benzylpenicillin and piperacillin.

The clinical efficacy of cefoperazone-sulbactam versus piperacillin-tazobactam in the treatment of severe community-acquired pneumonia.

The objective was to compare the clinical efficacy of cefoperazone-sulbactam with piperacillin-tazobactam in the treatment of severe community-acquired pneumonia (SCAP). The retrospective study was conducted from March 1, 2018 to May 30, 2019. Clinical outcomes were compared for patients who received either cefoperazone-sulbactam or piperacillin-tazobactam in the treatment of SCAP. A total of 815 SCAP patients were enrolled. Among them, 343 received cefoperazone-sulbactam, and 472 received piperacillin-tazobactam. Patients who received cefoperazone-sulbactam presented with higher Charlson Comorbidity Index scores. (6.20 ± 2.77 vs 5.72 ± 2.61; P = .009). The clinical cure rates and effectiveness for patients receiving cefoperazone-sulbactam and piperacillin-tazobactam were 84.2% versus 80.3% (P = .367) and 85.4% versus 83.3% (P = .258), respectively. In addition, the overall mortality rate of the cefoperazone-sulbactam group was 16% (n = 55), which was also comparable to the piperacillin-tazobactam group (17.8%, n = 84, P = .572). The primary clinical outcomes for patients receiving cefoperazone-sulbactam were superior compared to those receiving piperacillin-tazobactam after adjusting disease severity status. The clinical efficacy of cefoperazone-sulbactam in the treatment of adult patients with SCAP is comparable to that of piperacillin-tazobactam. After adjusting for disease severity, cefoperazone-sulbactam tended to be superior to piperacillin-tazobactam.

Association between emergency department sepsis order set design and delay to second dose piperacillin-tazobactam administration.

BACKGROUND: Delay to first antibiotic dose in patients with sepsis has been associated with increased mortality. Second dose antibiotic delay has also been linked to worsened patient outcomes. Optimal methods to decrease second dose delay are currently unclear. The primary objective of this study was to evaluate the association between updating an emergency department (ED) sepsis order set design from one-time doses to scheduled antibiotic frequencies and delay to administration of second piperacillin-tazobactam dose. METHODS: This retrospective cohort study was conducted at eleven hospitals in a large, integrated health system and included adult patients treated in the ED with at least one dose of piperacillin-tazobactam ordered through an ED sepsis order set over a two year period. Patients were excluded if they received less than two doses of piperacillin-tazobactam. Midway through the study period, the enterprise-wide ED sepsis order set was updated to include scheduled antibiotic frequencies. Two patient cohorts receiving piperacillin-tazobactam were compared: those in the year before the order set update and those in the year post-update. The primary outcome was major delay, defined as an administration delay >25% of the recommended dosing interval, which was evaluated with multivariable logistic regression and interrupted time series analysis. RESULTS: 3219 patients were included: 1222 in the pre-update group and 1997 in the post-update group. The proportion of patients who experienced major second dose delay was significantly lower in the post-update group (32.7% vs 25.6%, p < 0.01; adjusted OR 0.64, 95% CI 0.52 to 0.78). No between-group difference was detected in the slope of monthly major delay frequency, but there was a significant level change (post-update change -10%, 95% CI -17.9% to -1.9%). CONCLUSIONS: Including scheduled antibiotic frequencies in ED sepsis order sets is a pragmatic mechanism to decrease delays in second antibiotic doses.

Piperacillin-tazobactam dosing in anuric acute kidney injury patients receiving continuous renal replacement therapy.

INTRODUCTION: To determine appropriate dosing of piperacillin-tazobactam in critically ill patients receiving continuous renal replacement therapy (CRRT). METHODS: The databases of PubMed, Embase, and ScienceDirect were searched. We used the Medical Subject Headings of "piperacillin-tazobactam," "CRRT," and "pharmacokinetics" or related terms or synonym to identify the studies for reviews. A one-compartment pharmacokinetic model was conducted to predict piperacillin levels for the initial 48 h of therapy. The pharmacodynamic target was 50% of free drug level above the minimum inhibitory concentration (MIC) and 4 times of the MIC. The dose that achieved at least 90% of the probability of target attainment was defined as an optimal dose. RESULTS: Our simulation study reveals that the dosing regimen of piperacillin-tazobactam 12 g/day is appropriate for treating Pseudomonal infection with KDIGO recommended effluent rate of 25-35 mL/kg/h. The MIC values of each setting were an important factor to design piperacillin-tazobactam dosing regimens. CONCLUSION: The Monte Carlo simulation can be a useful tool to evaluate drug dosing in critically ill acute kidney injury patients receiving CRRT when limited pharmacokinetic data are a concern. Clinical validation of these results is needed.

Effects of Catheter Tracking Management on Urinary Tract Function and Infection Rates in Patients With Spinal Cord Injury.

Context: Patients with bone-marrow injuries, such as spinal cord injuries (SCIs), usually have urinary dysfunction, changes to the urethra's anatomical structure, and pathophysiological changes of the urinary system, which can lead to urodynamic changes. If a patient receives improper treatment, repeated infections of the urinary system can easily occur, causing hydronephrosis and damage to renal function. Objective: The study intended to explore the effects of catheter follow-up management for patients with SCIs on the function of the bladder and the urinary tract and on urinary tract infections (UTIs), selecting antibiotics reasonably according to a bacterial culture and drug sensitivity test. Design: The research team designed a randomized controlled trial. Setting: The study took place at the Hebei Cangzhou Hospital of Integrated Traditional Chinese Medicine (TCM)-Western Medicine (WM) in Cangzhou City, Hebei Province, People's Republic of China. Participants: Participants were 92 patients with SCIs who were treated at the hospital between January 2020 and December 2021. Intervention: The research team randomly divided participants into an intervention group (n = 45) and a control group (n = 47). The control group received routine treatment, while the intervention group received catheter follow-up management. Outcome Measures: At baseline and postintervention after six weeks of treatment, the research team: (1) examined participants' bladder function, (2) examine urodynamic indexes including measurement of the maximum bladder volume, maximum urethral closure pressure, maximum urinary flow rate, and maximum detrusor pressure, and (3) assessed participants' QoL using the World Health Organization Quality of Life Questionnaire Abbreviated (WHOQOL-BREF). Results: Improvements in bladder function, urodynamic indexes, QoL, and UTIs occurred in both groups. The intervention group's: (1) total effective rate for bladder function was 91.11%, which was significantly higher than that of the control group (P = .022); (2) maximal bladder volume, urethral closure pressure, and urinary flow rate were 365.59 ± 54.43 ml, 81.19 ± 8.8 cmH2O, and 18.60 ± 2. 43 ml/s, respectively, and were significantly higher than those of the control group (all P = .000); (3) maximal detrusor pressure was 47.48 ± 5.64 cmH2O, which was significantly lower than that of the control group (p=0.000); (4) scores on the WHOQOL-BREF's subdimensions and total score were significantly higher than those in the control group: psychological, 17.92 ± 1.55; physiological, 30.30 ± 1.82; independence, 22.43 ± 1.40; social relations, 16.82 ± 1.32; environment, 21.19 ± 1.85; and total score, 110.02 ±16.64 (all P = .000); (5) incidence of urinary tract infection was 17.78 which was significantly lower than that of the control group (P = .003). The distribution of bacterial species in the UTIs of the intervention and control groups wasn't significantly different (P = .869). The two bacterial groups were Escherichia coli and Enterococcus. Drug sensitivity tests showed that the Escherichia coli were less susceptible to gentamicin, levofloxacin, and piperacillin than to ciprofloxacin, and the Enterococcus were less susceptible to gentamicin, ciprofloxacin, and levofloxacin than to piperacillin. Conclusions: For patients with SCIs, catheter follow-up management can be helpful in restoring the function of the bladder and urinary tract, can improve patients' QoL, and reduce their rate of UTIs. Clinically, medical practitioners should select antibiotics reasonably according to a bacterial culture and drug-sensitivity test.

Simultaneous infusion of two incompatible antibiotics: Impact of the choice of infusion device and concomitant simulated fluid volume support on the particulate load and the drug mass flow rates.

Vancomycin and piperacillin/tazobactam are known to be incompatible. The objectives of the present study were to evaluate the impact of their simultaneous infusion on mass flow rates and particulate load and identify preventive strategies. We assessed both static conditions and a reproduction of an infusion line used in a hospital's critical care unit. A high-performance liquid chromatography/UV diode array system and static and dynamic laser diffraction particle counters were used. The mass flow rates were primarily influenced by the choice of the infusion device and the presence of simulated fluid volume support. Drug incompatibility also appeared to affect vancomycin's mass flow rate, and the dynamic particulate load increased during flow rate changes - especially in the infusion set with a large common volume line and no concomitant simulated fluid volume support. Only discontinuation of the piperacillin/tazobactam infusion was associated with a higher particulate load in the infusion set with a large common volume line and no concomitant simulated fluid volume support. A low common volume line and the use of simulated fluid volume support were associated with smaller fluctuations in the mass flow rate. The clinical risk associated with a higher particulate load must now be assessed.

Molecular investigation of prevalence, phenotypic and genotypic diversity, antibiotic resistance, frequency of virulence genes and genome sequencing in Pseudomonas aeruginosa strains isolated from lobster.

AIM: Aquatic organisms are too susceptible to the increased growth of bacterial contamination. It seems that preventive measures should be prioritized to reduce bacterial load, and improve the health situation of marine-based product consumers. Hence, this study is aimed at molecular investigation of the prevalence of Pseudomonas aeruginosa as one of the most food-borne pathogens, antibiotic resistance, and virulence factor encoding gens in lobster samples. METHODOLOGY: After the collection of aquatic samples from Isfahan and Chabahar city during the summer and autumn seasons, they were cultured, and confirmed by biochemistry tests. Then, they were investigated for antibiotic resistance by the Kirby Bauer method. Then, antibiotic resistance, virulence factor encoding genes, and Multi-Drug Resistance (MDR) patterns were analyzed. Statistical analysis was done by SPSS through chi-square tests. RESULTS: Bacterial contamination in samples taken from Isfahan city was higher than in Chabahar city despite having a cooler climate on summer days. Antibiotic resistance to piperacillin in fresh shrimp samples taken in summer In Isfahan city was contrary to its usage as a front-line antibiotic agent for Pseudomonas aeruginosa. Lowered MDR pattern in frozen samples, was related to the varied expression of antibiotic resistance, highlighting the importance of regulations for cold chain in storage, transportation, and distribution of marine samples, especially when compared to fresh shrimps. CONCLUSION: Food-borne pathogens, antibiotic resistance, and their virulence factors are of clinical and environmental importance. Results of our study indicated a high rate of frequency for Pseudomonas aeruginosa isolated from marine samples, antibiotic resistance, antibiotic resistance encoding genes, virulence factors encoding genes, and MDR. Maintenance of the cold chain, and proper food processing, have indispensable roles in the preservation, and reduction of Pseudomonas aeruginosa frequency in aquatic organisms.

Emerging resistance to ceftriaxone treatment owing to different ampD mutations in Enterobacter roggenkampii.

OBJECTIVES: The Enterobacter cloacae complex is responsible for a variety of infections in hospitalized patients and is resistant to ß-lactam antibiotics owing to the expression of AmpC ß-lactamase. We report emerging resistance in Enterobacter roggenkampii exposed to ceftriaxone and explore the mechanism underlying mutations responsible for this resistance. METHODS: Three strains were derived from different samples from one patient (blood and liver abscess fluid). Antimicrobial susceptibility was evaluated by standard broth microdilution, while ampC expression was determined via RT-PCR. Genetic relatedness was evaluated via pulsed-field gel electrophoresis (PFGE). Species identification and comparative genome analysis were performed via genome sequencing. Mutation rate testing and selection of AmpC-derepressed mutants were conducted to explore the mutation mechanism. RESULTS: E. roggenkampii F1247 was susceptible to third-generation cephalosporins (3GCs); F95 and F1057, found in blood sample on day 11 and liver abscess drainage fluid on day 25, were resistant. ampC expression was 341- and 642-fold higher in F95 and F1057, respectively, than in F1247. Three isolates were the same PFGE and sequence types (ST1778) and were highly homologous (2 and 4 core genome single nucleotide polymorphism differences). Compared to F1247, F95 possessed a 575 bp deletion, including 537 bp of ampD, whereas F1057 harbored only one amino acid mutation (Leu140Pro in ampD). The mutation rates from F1247 exposure to cefotaxime, ceftazidime, ceftriaxone, piperacillin-tazobactam, and cefepime were (1.90 ± 0.21) × 10-8, (3.18 ± 0.43) × 10-8, (2.00 ± 0.20) × 10-8, (2.92 ± 0.29) × 10-9, and zero, respectively. In vitro-selected mutations responsible for resistance were identified in ampD, ampR, and dacB. CONCLUSIONS: E. roggenkampii may develop resistance in vivo and in vitro upon exposure to 3GCs and to a lesser extent to piperacillin-tazobactam. 3GCs should not be used as a monotherapy for E. roggenkampii infections. Therapy using cefepime or carbapenems may be preferred to piperacillin-tazobactam in the treatment of E. roggenkampii, especially if source control is difficult.

Population pharmacokinetics of piperacillin in critically ill children including those undergoing continuous kidney replacement therapy.

OBJECTIVES: Despite that piperacillin-tazobactam combination is commonly used in critically ill children, increasing evidence suggests that the current dosing schedules are not optimal for these patients. The aim of this work is to develop a population pharmacokinetic model for piperacillin to evaluate the efficacy of standard dosing in children with and without continuous kidney replacement therapy (CKRT) and to propose alternative dosing schemes maximizing target attainment. METHODS: Four hundred twenty-nine piperacillin concentrations measured in different matrices, obtained from 32 critically ill children (19 without CKRT, 13 with CKRT) receiving 100 mg/kg of piperacillin/tazobactam every 8 hours (increased to 12 hours after the fourth dose) were modelled simultaneously using the population approach with NONMEM 7.4. The percentage of patients with 90% fT > MIC and target attainment (percentage of dosing interval above MIC) were estimated for different intermittent and continuous infusions in the studied population. RESULTS: Piperacillin pharmacokinetic was best described with a two-compartment model. Renal, nonrenal, and hemofilter clearances were found to be influenced by the glomerular filtration rate, height (renal clearance), weight (nonrenal clearance), and filter surface (hemofilter clearance). Only seven (37%) children without CKRT and seven (54%) with CKRT achieved 90% fT > MIC with the current dosing schedule. Of the alternative regimens evaluated, a 24-hour continuous infusion of 200 mg/kg (CKRT) and 300 mg/kg (no CKRT) provided 100% fT > MIC (percent of time free drug remains above the minimum inhibitory concentration) (≤16 mg/L) and target attainments ≥90% across all evaluated MICs. DISCUSSION: In children with and without CKRT, standard dosing failed to provide an adequate systemic exposure, while prolonged and continuous infusions showed an improved efficacy.

Pharmacokinetics of piperacillin and tazobactam in critically Ill patients treated with continuous kidney replacement therapy: A mini-review and population pharmacokinetic analysis.

WHAT IS KNOWN AND OBJECTIVE: Timely and appropriate dosing of antibiotics is essential for the treatment of bacterial sepsis. Critically ill patients treated with continuous kidney replacement therapy (CKRT) often have physiologic derangements that affect pharmacokinetics (PK) of antibiotics and dosing may be challenging. We sought to aggregate previously published piperacillin and tazobactam (pip-tazo) pharmacokinetic data in critically ill patients undergoing CKRT to better understand pharmacokinetics of pip-tazo in this population and better inform dosing. METHODS: The National Library of Medicine Database was searched for original research containing piperacillin or tazobactam clearance (CL) or volume of distribution (V) estimates in patients treated with CKRT. The search yielded 77 articles, of which 26 reported suitable estimates of CL or V. Of the 26 articles, 10 for piperacillin and 8 for tazobactam had complete information suitable for population pharmacokinetic modelling. Also included in the analysis was piperacillin and tazobactam PK data from 4 critically ill patients treated with CKRT in the Military Health System, 2 with burn and 2 without burn. RESULTS AND DISCUSSION: Median and range of literature reported PK parameters for piperacillin (CL 2.76 L/hr, 1.4-7.92 L/hr, V 31.2 L, 16.77-42.27 L) and tazobactam (CL 2.34 L/hr, 0.72-5.2 L/hr, V 36.6 L, 26.2-58.87 L) were highly consistent with population estimates (piperacillin CL 2.7 L/hr, 95%CI 1.99-3.41 L/hr, V 25.83 22.07-29.59 L, tazobactam CL 2.49 L/hr, 95%CI 1.55-3.44, V 30.62 95%CI 23.7-37.54). The proportion of patients meeting pre-defined pharmacodynamic (PD) targets (median 88.7, range 71%-100%) was high despite significant mortality (median 44%, range 35%-60%). High mortality was predicted by baseline severity of illness (median APACHE II score 23, range 21-33.25). Choice of lenient or strict PD targets (ie 100%fT >MIC or 100%fT >4XMIC) had the largest impact on probability of target attainment (PTA), whereas presence or intensity of CKRT had minimal impact on PTA. WHAT IS NEW AND CONCLUSION: Pip-tazo overexposure may be associated with increased mortality, although this is confounded by baseline severity of illness. Achieving adequate pip-tazo exposure is essential; however, risk of harm from overexposure should be considered when choosing a PD target and dose. If lenient PD targets are desired, doses of 2250-3375 mg every 6 h are reasonable for most patients receiving CKRT. However, if a strict PD target is desired, continuous infusion (at least 9000-13500 mg per day) may be required. However, some critically ill CKRT populations may need higher or lower doses and dosing strategies should be tailored to individuals based on all available clinical data including the specific critical care setting.

Therapeutic drug monitoring of meropenem and piperacillin-tazobactam in the Singapore critically ill population - A prospective, multi-center, observational study (BLAST 1).

PURPOSE: To determine percentage of patients with sub-therapeutic beta-lactam exposure in our intensive care units (ICU) and to correlate target attainment with clinical outcomes. MATERIALS AND METHODS: Multi-centre, prospective, observational study was conducted in ICUs from three hospitals in Singapore from July 2016 to May 2018. Adult patients (≥21 years) receiving meropenem or piperacillin-tazobactam were included. Four blood samples were obtained during a dosing interval to measure and determine attainment of therapeutic targets: unbound beta-lactam concentration above (i) minimum inhibitory concentration (MIC) at 40% (meropenem) or 50% (piperacillin) of dosing interval (40-50%fT > MIC) and (ii) 5 × MIC at 100% of dosing interval (100%fT > 5 × MIC). Correlation to clinical outcomes was evaluated using Cox regression. RESULTS: Beta-lactam levels were highly variable among 61 patients, with trough meropenem and piperacillin levels at 21.5 ± 16.8 mg/L and 101.6 ± 81.1 mg/L respectively. Among 85 sets of blood samples, current dosing practices were able to achieve 94% success for 40-50%fT > MIC and 44% for 100%fT > 5 × MIC. Failure to achieve 40-50%fT > MIC within 48 h was significantly associated with all-cause mortality (HR: 9.0, 95% CI: 1.8-45.0), after adjustment for APACHE II score. Achievement of 100%fT > 5 × MIC within 48 h was significantly associated with shorter length of hospital stay. CONCLUSION: Current dosing practices may be suboptimal for ICU patients. Beta-lactam TDM may be useful.

Effects of piperacillin/tazobactam or cefepime on folinate dose in patients receiving high-dose methotrexate: A retrospective cohort study using Japanese administrative claims data.

INTRODUCTION: Delayed methotrexate (MTX) clearance with the co-administration of piperacillin/tazobactam (PIPC/TAZ) has been reported. Penicillins have been associated with reduced MTX clearance but the evidence is limited. There are no cases described with cefepime but penicillins are listed as interacting with MTX. We aimed to reveal whether the co-administration of PIPC/TAZ or CFPM affects MTX clearance using data from an administrative database. METHODS: We used data from the JMDC database, a large insurance claims database constructed in Japan. We included patients who were prescribed PIPC/TAZ or CFPM between days 1 and 3 in high-dose MTX (HD-MTX). We compared one co-administration episode (with PIPC/TAZ or CFPM) to one control episode (without), as a match-control study of two different episodes in the same patient. The primary outcomes were the duration and cumulative dose of leucovorin (LV) as a surrogate indicator of delayed MTX clearance. RESULTS: Three patients who were co-administered PIPC/TAZ and 16 patients who were co-administered CFPM with HD-MTX were included. In the PIPC/TAZ group, the duration and the cumulative doses of LV were similar in co-administration and control episode (median 3.0 vs. 3.0 days and 288.0 vs. 219.0 mg). In the CFPM group, the duration and the cumulative doses of LV were not significantly different in co-administration and control episode (3.0 vs. 4.0 days and 169.5 vs. 258.0 mg). CONCLUSIONS: Our findings revealed that PIPC/TAZ did not necessarily cause a delay in MTX clearance during HD-MTX therapy. Moreover, the co-administration of CFPM with HD-MTX did not affect MTX clearance.

Anaphylaxis Induced by Intravenous Tacrolimus Administration During Kidney Transplant Surgery: A Case Report.

A 35-year-old male patient with end-stage renal disease due to vesicoureteral reflux preemptively received a renal graft from his father. The patient had a history of allergy to contrast-enhancing media. He received oral tacrolimus (TAC) and mycophenolate mofetil without any problems for 2 days before kidney transplantation. During the induction period of the surgery, his systolic blood pressure (sBP) decreased to 60 mmHg approximately 1 hour after initiating intravenous tacrolimus (TAC-IV) and intravenous piperacillin (PIPC), and the anesthesiologist suspected drug-induced anaphylaxis and stopped administration of the medications. Because TAC had been administered preoperatively without any adverse events, PIPC was suspected as the causative agent of the anaphylaxis. After the patient's hemodynamics returned to baseline, TAC-IV was restarted. However, his sBP rapidly decreased to 40 mmHg and the patient developed wheezing. He was diagnosed with drug-induced anaphylaxis due to castor oil derivatives in the TAC-IV formulation. The patient's sBP was restored with the administration of some vasopressors, and kidney transplantation was then performed without difficulty. Two days after kidney transplantation, oral TAC was administered without anaphylaxis. Clinicians should consider that not only the drug itself but also its additives or metabolites could induce anaphylaxis.

Study on the mechanisms of the cross-resistance to TET, PIP, and GEN in Staphylococcus aureus mediated by the Rhizoma Coptidis extracts.

The purpose of this study was focused on the mechanisms of the cross-resistance to tetracycline (TET), piperacillin Sodium (PIP), and gentamicin (GEN) in Staphylococcus aureus (SA) mediated by Rhizoma Coptidis extracts (RCE). The selected strains were exposed continuously to RCE at the sublethal concentrations for 12 days, respectively. The susceptibility change of the drug-exposed strains was determined by analysis of the minimum inhibitory concentration. The 16S rDNA sequencing method was used to identify the RCE-exposed strain. Then the expression of resistant genes in the selected isolates was analyzed by transcriptome sequencing. The results indicated that RCE could trigger the preferential cross-resistance to TET, PIP, and GEN in SA. The correlative resistant genes to the three kinds of antibiotics were upregulated in the RCE-exposed strain, and the mRNA levels of the resistant genes determined by RT-qPCR were consistent with those from the transcriptome analysis. It was suggested from these results that the antibacterial Traditional Chinese Medicines might be a significant factor of causing the bacterial antibiotic-resistance.

Significant interaction between high-dose methotrexate and high-dose piperacillin-tazobactam causing reversible neurotoxicity and renal failure in an osteosarcoma patient.

INTRODUCTION: Pharmacokinetic interaction of high-dose methotrexate (MTX) and other concomitantly administered renally secreted medicinal products may lead to insufficient methotrexate serum level decrease and significant MTX toxicity. CASE REPORT: We report the case of an 18-year-old male patient treated with high-dose MTX for an osteosarcoma and with high-dose piperacillin-tazobactam at the same time. MTX serum levels were severely elevated 24 hours after the MTX infusion and did not decrease in accordance with the specific calcium folinate rescue protocol. The patient experienced renal failure accompanied by neurological symptoms, most consistent with MTX-related renal and CNS toxicity.Management and outcome: After discontinuation of piperacillin-tazobactam, intensified calcium folinate rescue therapy, and IV hydration, the MTX serum levels decreased appropriately, and toxicity symptoms resolved. DISCUSSION: Severe MTX-related toxicity, caused by drug-drug interaction, suggests that the concomitant use of high-dose MTX and high-dose piperacillin-tazobactam should be avoided generally.

Piperacillin/tazobactam-induced coagulopathy in a patient through a vitamin K-dependent mechanism.

Haematologic side effects associated with piperacillin/tazobactam (PTZ) treatment are rare but can be fatal. The exact mechanism by which PTZ causes haemorrhages has not been determined. We report the case of a patient who received PTZ treatment and developed a coagulopathy through a vitamin K-dependent mechanism. A 70-year-old female patient was admitted to the intensive care unit because she had a severe case of pneumonia and a pulmonary thromboembolism. Empirical antibiotic treatment using PTZ was started. Her international normalised ratio (INR) was already increased and became elevated again when PTZ was restarted. Her coagulopathy was reversed by supplementation with vitamin K. We conclude that PTZ can induce coagulopathy through a vitamin K-dependent mechanism and, to our knowledge, this is the first case report to suggest that mechanism. We suggest that patients at risk for a vitamin K deficiency should be monitored for coagulopathy when piperacillin or any other board spectrum antibiotic is administered.

The ONTAI study - a survey on antimicrobial dosing and the practice of therapeutic drug monitoring in German intensive care units.

PURPOSE: Optimization of antibiotic therapy is still urgently needed in critically ill patients. The aim of the ONTAI survey (online survey on the use of Therapeutic Drug Monitoring of antibiotics in intensive care units) was to evaluate which strategies intensive care physicians in Germany use to improve the quality of antibiotic therapy and what role a Therapeutic Drug Monitoring (TDM) plays. METHODS: Among the members of the German Society for Anaesthesiology and the German Society for Medical Intensive Care Medicine and Emergency Medicine, a national cross-sectional survey was conducted using an online questionnaire. RESULTS: The questionnaire was completely answered by 398 respondents. Without TDM, prolonged infusion was judged to be the most appropriate dosing regimen for beta lactams. A TDM for piperacillin, meropenem and vancomycin was performed in 17, 22 and 75% of respondents, respectively. For all beta lactams, a TDM was requested more often than it was available. There was great uncertainty as to the optimal pharmacokinetic/pharmacodynamic index for beta-lactams. 86% of the respondents who received minimal inhibitory concentrations adapted the therapy accordingly. CONCLUSION: German intensive care physicians are convinced of TDM for dose optimization. However, practical implementation, the determination of MICs and defined target values are still lacking.

Early switch from intravenous to oral antibiotic therapy in patients with cancer who have low-risk neutropenic sepsis (the EASI-SWITCH trial): study protocol for a randomised controlled trial.

BACKGROUND: Neutropenic sepsis remains a common treatment complication for patients receiving systemic anti-cancer treatment. The UK National Institute for Health and Care Excellence have not recommended switching from empirical intravenous antibiotics to oral antibiotics within 48 h for patients assessed as low risk for septic complications because of uncertainty about whether this would achieve comparable outcomes to using intravenous antibiotics for longer. The UK National Institute for Health Research funded the EASI-SWITCH trial to tackle this uncertainty. METHODS: The trial is a pragmatic, randomised, non-inferiority trial that aims to establish the clinical and cost-effectiveness of early switching from intravenous to oral antibiotics in cancer patients with low-risk neutropenic sepsis. Patients ≥ 16 years, receiving systemic anti-cancer treatment (acute leukaemics/stem cell transplants excluded), with a temperature of > 38 °C, neutrophil count ≤ 1.0 × 109/L, MASCC (Multinational Association of Supportive Care in Cancer) score ≥ 21 and receiving IV piperacillin/tazobactam or meropenem for less than 24 h are eligible to participate. Patients are randomised 1:1 either (i) to switch to oral ciprofloxacin and co-amoxiclav within 12-24 h of commencing intravenous antibiotics, completing at least 5 days total antibiotics (intervention), or (ii) to continue intravenous antibiotics for at least 48 h, with ongoing antibiotics being continued at the physician's discretion (control). Patients are discharged home when their physician deems it appropriate. The primary outcome measure is a composite of treatment failures as assessed at day 14. The criteria for treatment failure include fever persistence or recurrence 72 h after starting intravenous antibiotics, escalation from protocolised antibiotics, hospital readmission related to infection/antibiotics, critical care support or death. Based on a 15% treatment failure rate in the control group and a 15% non-inferiority margin, the recruitment target is 230 patients. DISCUSSION: If the trial demonstrates non-inferiority of early switching to oral antibiotics, with potential benefits for patient quality of life and resource savings, this finding will have significant implications for the routine clinical management of those with low-risk neutropenic sepsis. TRIAL REGISTRATION: ISRCTN: 84288963. Registered on the 1 July 2015. https://doi.org/10.1186/ISRCTN84288963. EudraCT: 2015-002830-35.

In vitro activity of meropenem/piperacillin/tazobactam triple combination therapy against clinical isolates of Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus pseudintermedius and vancomycin-resistant Enterococcus spp.

OBJECTIVES: To evaluate the activity of the reported synergistic and collaterally sensitive antibiotic combination, meropenem/piperacillin/tazobactam (ME/PI/TZ), against a panel of methicillin-resistant Staphylococcus aureus (MRSA) and other methicillin-resistant Staphylococcus species; and to investigate the relationship between ME/PI/TZ susceptibility and the genomic background of clinical isolates of MRSA. METHODS: ME/PI/TZ combination and single drug minimum inhibitory concentrations (MICs) were determined for 207 strains (including 121 MRSA, 4 methicillin-sensitive S. aureus [MSSA], 37 vancomycin-intermediate S. aureus [VISA], 6 ceftaroline non-susceptible MRSA, 29 coagulase-negative staphylococci [CoNS], 5 S. pseudointermedius and 5 vancomycin-resistant Enterococci [VRE]) by broth microdilution. Whole genomes of 168 S. aureus strains were sequenced, assembled, and comparatively analysed. RESULTS: USA300-SCCmec type IV isolates, clonal complex 8 (CC8)-MRSA isolates, including some VISA and ceftaroline (CPT)-intermediate strains, and all tested methicillin-resistant S. epidermidis isolates were highly susceptible to ME/PI/TZ. Isolates with elevated MICs (MICs of >16/16/16 mg/L) clustered with the USA100-SCCmec type II strain. Susceptibility of MRSA to ME/PI/TZ was correlated with susceptibility to ME. No obvious cross-resistance to CPT was observed among high-ME/PI/TZ MIC isolates. CONCLUSIONS: The ME/PI/TZ combination is effective against a variety of clinical MRSA isolates, particularly of the USA300 lineage, which is expanding worldwide. ME/PI/TZ is also effective against drug-resistant CoNS and S. pseudintermedius clinical isolates.