Single versus combination intravenous anti-pseudomonal antibiotic therapy for people with cystic fibrosis.

BACKGROUND: The choice of antibiotic, and the use of single or combined therapy are controversial areas in the treatment of respiratory infection due to Pseudomonas aeruginosa in cystic fibrosis (CF). Advantages of combination therapy include wider range of modes of action, possible synergy and reduction of resistant organisms; advantages of monotherapy include lower cost, ease of administration and reduction of drug-related toxicity. Current evidence does not provide a clear answer and the use of intravenous antibiotic therapy in CF requires further evaluation. This is an update of a previously published review. OBJECTIVES: To assess the effectiveness of single compared to combination intravenous anti-pseudomonal antibiotic therapy for treating people with CF. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Most recent search of the Group's Trials Register: 07 October 2020. We also searched online trials registries on 16 November 2020. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing a single intravenous anti-pseudomonal antibiotic with a combination of that antibiotic plus a second anti-pseudomonal antibiotic in people with CF. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We assessed the certainty of the data using GRADE. MAIN RESULTS: We identified 59 trials, of which we included eight trials (356 participants) comparing a single anti-pseudomonal agent to a combination of the same antibiotic and one other. There was a wide variation in the individual antibiotics used in each trial. In total, the trials included seven comparisons of a beta-lactam antibiotic (penicillin-related or third generation cephalosporin) with a beta-lactam-aminoglycoside combination and three comparisons of an aminoglycoside with a beta-lactam-aminoglycoside combination.  There was considerable heterogeneity amongst these trials, leading to difficulties in performing the review and interpreting the results. These results should be interpreted cautiously. Six of the included trials were published between 1977 and 1988; these were single-centre trials with flaws in the randomisation process and small sample size. Overall, the methodological quality was poor and the certainty of the evidence ranged from low to moderate. The review did not find any differences between monotherapy and combination therapy in either the short term or in the long term for the outcomes of different lung function measures, bacteriological outcome measures, need for additional treatment, adverse effects, quality of life or symptom scores. AUTHORS' CONCLUSIONS: The results of this review are inconclusive. The review raises important methodological issues. There is a need for an RCT which needs to be well-designed in terms of adequate randomisation allocation, blinding, power and long-term follow-up. Results need to be standardised to a consistent method of reporting, in order to validate the pooling of results from multiple trials.

Implementation of EMR-based standardized antibiotic desensitization protocols and its impact on providers.

Background: As desensitization protocols become more readily available and published, more institutions are implementing them and searching for ways to streamline the process. There have been no published studies to date on the effect that electronic medical record systems (EMR) have on the safety and efficiency of ß-lactam antibiotic desensitization. Objective: The purpose of this study was to evaluate the changes in workflow, efficiency, and medical errors after implementation of ß-lactam antibiotic desensitization. Methods: A collaborative effort between the Allergy/Immunology Division and the Pharmacy Department led to the creation and implementation of antibiotic desensitization order sets. Pre- and postimplementation of ß-lactam antibiotic surveys were sent to pharmacists and allergy/immunology fellows and attendings at a single-center tertiary care center. Results: There were only 26 valid respondents (12.3%) to both the pre- and postimplementation surveys. The percentage of respondents who thought that the time needed to prepare desensitization materials was < 4 hours increased from 23% to 77% (p < 0.001). The percentage of respondents who thought that the time needed to input electronic desensitization orders was < 1 hour increased from 19% to 54% (p = 0.002). The percentage of respondents who identified zero errors increased from 42% to 92% (p = 0.001). The perception of the overall desensitization process efficiency significantly increased (p < 0.001). Conclusion: Creation of standardized electronic ß-lactam antibiotic desensitization order sets significantly decreased the time taken to order and prepare materials and increased overall efficiency.

[Antibiotic stewardship - recent developments]. / Aktuelle Entwicklungen im Bereich Antibiotic Stewardship.

Both in hospitals and outpatient settings, fewer fluoroquinolones have been prescribed in Germany in recent years. The consumption of cephalosporins also decreased somewhat in favor of penicillin derivatives. The aminoglycosides, which have only rarely been prescribed, can now be used again as a suitable alternative - but only parenterally - due to their relatively favorable activity and low resistance rates among typical urinary tract infection pathogens. In acute severe infection such as sepsis, addition, e. g. of tobramycin, to a suitable betalactam of a single dose has been discussed as a useful option, but the evidence for such a recommendation is weak. There is little news about the rational use of antibiotics in hematology-oncology patients. In the case of fever and neutropenia, the initial empirical regimens of choice remain piperacillin-tazobactam or a pseudomonas-active carbapenem as monotherapy. These betalactams should be given with extended infusion times, e. g. over 4 hours. Linezolid should be considered as a reserve drug and not be used empirically, but only in targeted therapy. With regard to an alleged penicillin allergy, the risk of true allergic reactions can be differentiated by careful taking of the history; on that ground patient subgroups can be defined that may be re-exposed without further allergological examinations.

Prolonged infusion of beta-lactam antibiotics for Gram-negative infections: rationale and evidence base.

PURPOSE OF REVIEW: The aim of this review is to discuss the rationale of and current evidence for prolonged beta-lactam infusion in the management of Gram-negative infections. RECENT FINDINGS: Pharmacokinetic/pharmacodynamic (PK/PD) data from various in-vitro and in-vivo experimental studies conclusively support prolonged infusion over intermittent infusion in terms of achieving effective beta-lactam exposure for maximal bacterial killing. Superior PK/PD target attainment has been demonstrated with prolonged beta-lactam infusion in patient populations that are more likely to have less susceptible Gram-negative infections. These populations include critically ill patients, cystic fibrosis patients and patients with malignant diseases. The clinical impact of prolonged beta-lactam infusion is likely to be the greatest in these patient groups: critically ill patients with a high level of illness severity who are not receiving renal replacement therapy; patients with nonfermenting Gram-negative bacilli infection and patients with respiratory infection. Critically ill patients with augmented renal clearance may not achieve effective beta-lactam exposure even with the use of prolonged infusion. Maximizing the effectiveness of prolonged beta-lactam infusion via therapeutic drug monitoring is becoming a more common strategy in the management of critically ill patients with Gram-negative infection. SUMMARY: Prolonged beta-lactam infusion may not benefit all patients but only for those who are critically ill and/or immunocompromised, who are also more likely to have less susceptible Gram-negative infections.

Carbapenems versus alternative ß-lactams monotherapy or in combination for febrile neutropenia: Systematic review and meta-analysis of randomized controlled trial.

BACKGROUND: Febrile neutropenia (FN) in cancer patients can be life threatening and require the timely antimicrobial agents treatment. METHODS: To compare the effectiveness and safety of carbapenems versus ß-lactams for FN. PubMed, Medline (Ovid SP), Cochrane CENTRAL, and Embase were searched up to March 2019. FN in patients due to undergoing chemotherapy and treated with carbapenems and ß-lactams were included. Odds ratio (OR) and 95% confidence interval (CI) were estimated. RESULTS: Fifty randomized controlled trials (RCTs) studies involving 10,995 participants were included. Carbapenems were more likely to experience treatment success without modification (OR = 1.34, 95% CI = 1.24-1.46) compared with ß-lactams. Meropenem (OR = 1.36, 95% CI = 1.18-1.56; OR = 1.24, 95% CI = 1.01-1.53), imipenem/cilastatin (OR = 1.40, 95% CI = 1.19-1.65; OR = 1.31, 95% CI = 1.04-1.67) showed higher effectiveness from that by ß-lactams monotherapy or in combination with aminoglycoside, respectively. Carbapenems-aminoglycoside combination therapy does not provide an advantage over carbapenems alone. Meropenem showed similar risk of adverse events (AEs) versus ß-lactams. Imipenem/cilastatin was related to higher risk of AEs compared with ß-lactams. There was no significant difference between carbapenems and ß-lactams monotherapy or in combination. CONCLUSION: Meropenem and imipenem/cilastatin monotherapy appears to be available treatment for FN compared with ß-lactams. Imipenem/cilastatin was related to higher risk of AEs. Balancing the evidence for drug efficacy and side effects, meropenem monotherapy appears to be available treatment for FN. Individual centers should select the best matching therapy regimens according to local epidemiology and susceptibility patterns.

Efficacy of extended infusion of ß-lactam antibiotics for the treatment of febrile neutropenia in haematologic patients: protocol for a randomised, multicentre, open-label, superiority clinical trial (BEATLE).

BACKGROUND: Febrile neutropaenia (FN) is a very common complication in patients with haematological malignancies and is associated with considerable morbidity and mortality. Broad-spectrum antipseudomonal ß-lactam antibiotics (BLA) are routinely used for the treatment of cancer patients with FN. However, the clinical efficacy of BLA may be diminished in these patients because they present with pathophysiological variations that compromise the pharmacokinetic (PK) parameters of these antibiotics. Optimised administration of BLA in prolonged infusions has demonstrated better clinical outcomes in critically ill patients. However, there is a paucity of data on the usefulness of this strategy in patients with FN. The aim of this study is to test the hypothesis that the administration of BLA would be clinically more effective by extended infusion (EI) than by intermittent infusion (II) in haematological patients with FN. METHODS: A randomised, multicentre, open-label, superiority clinical trial will be performed. Patients with haematological malignancies undergoing chemotherapy or haematopoietic stem-cell transplant and who have FN and receive empirical antibiotic therapy with cefepime, piperacillin-tazobactam or meropenem will be randomised (1:1) to receive the antibiotic by EI (during half the time of the dosing interval) in the study group, or by II (30 min) in the control group. The primary endpoint will be clinical efficacy, defined as defervescence without modifying the antibiotic treatment administered within the first 5 days of therapy. The primary endpoint will be analysed in the intention-to-treat population. The secondary endpoints will be pharmacokinetic/pharmacodynamic (PK/PD) target achievement, bacteraemia clearance, decrease in C-reactive protein, overall (30-day) case-fatality rate, adverse events and development of a population PK model of the BLA studied. DISCUSSION: Data on the usefulness of BLA administration in patients with FN are scant. Only three clinical studies addressing this issue have been published thus far, with contradictory results. Moreover, these studies had some methodological flaws that limit the interpretation of their findings. If this randomised, multicentre, phase IV, open-label, superiority clinical trial validates the hypothesis that the administration of BLA is clinically more effective by EI than by II in haematological patients with FN, then the daily routine management of these high-risk patients could be changed to improve their outcomes. TRIAL REGISTRATION: European Clinical Trials Database: EudraCT 2018-001476-37. ClinicalTrials.gov, ID: NCT04233996.

High Heterogeneity of Multidrug-Resistant Enterobacteriaceae Fecal Levels in Hospitalized Patients Is Partially Driven by Intravenous ß-Lactams.

Multidrug-resistant Enterobacteriaceae (MRE) colonize the intestine asymptomatically from where they can breach into the bloodstream and cause life-threatening infections, especially in heavily colonized patients. Despite the clinical relevance of MRE colonization levels, we know little about how they vary in hospitalized patients and the clinical factors that determine those levels. Here, we conducted one of the largest studies of MRE fecal levels by tracking longitudinally 133 acute leukemia patients and monitoring their MRE levels over time through extensive culturing. MRE were defined as Enterobacteriaceae species that acquired nonsusceptibility to ≥1 agent in ≥3 antimicrobial categories. In addition, due to the selective media used, the MRE had to be resistant to third-generation cephalosporins. MRE were detected in 60% of the patients, but their fecal levels varied considerably among patients and within the same patient (>6 and 4 orders of magnitude, respectively). Multivariate analysis of clinical metadata revealed an impact of intravenous beta-lactams (i.e., meropenem and piperacillin-tazobactam), which significantly diminished the fecal MRE levels in hospitalized patients. Consistent with a direct action of beta-lactams, we found an effect only when the patient was colonized with strains sensitive to the administered beta-lactam (P < 0.001) but not with nonsusceptible strains. We report previously unobserved inter- and intraindividual heterogeneity in MRE fecal levels, suggesting that quantitative surveillance is more informative than qualitative surveillance of hospitalized patients. In addition, our study highlights the relevance of incorporating antibiotic treatment and susceptibility data of gut-colonizing pathogens for future clinical studies and in clinical decision-making.

¿Cumplimos el objetivo de farmacocinética y farmacodinamia en pacientes críticos que reciben antibióticos betalactámicos? / Do we meet the goal of pharmacokinetics and pharmacodynamics in critically ill patients receiving beta-lactam antibiotics?

Introducción: Los pacientes críticamente enfermos presentan cambios fisiopatológicos que alteran las concentraciones de antibióticos betalactámicos. El objetivo fue determinar si las dosis de uso habitual en pacientes críticos alcanzan las concentraciones asociadas con mayor actividad y establecer las variables de PK/PD que se asocian con concentraciones subóptimas de antibiótico.Métodos: Estudio prospectivo realizado en una terapia intensiva de adultos en un periodo de 13 meses. Se incluyeron pacientes que recibieron cefazolina, ceftriaxona, ceftazidima o meropenem. Se realizó dosaje de concentración de antibiótico en plasma en el 50% del intervalo de dosis. Se calculó la concentración de antibiótico libre y se comparó con el objetivo 50% fT>CIM y el objetivo 50% fT>CIM x 4 para los microorganismos susceptibles definidos, según criterios del CLSI. Se comparó el grupo de pacientes que cumplió el objetivo 50% fT>CIM x 4 con el que no, en términos de variables de PK/PD.Resultados: Se incluyeron 29 determinaciones y 55 comparaciones. En el 92,7% de los casos se alcanzó el objetivo 50% fT>CIM y en el 61,8% el objetivo 50% fT>CIM x 4. En el peor escenario, es decir considerando el germen susceptible con CIM más alta, solo el 48,3% de los pacientes cumplieron el objetivo 50% fT>CIM x 4. Los pacientes que no llegaron al objetivo 50% fT>CIM x 4 tuvieron mayor RESUMENARTÍCULO ORIGINALaclaramiento renal que los que sí lo hicieron (160 vs 108,5 ml/min/1,73m2, p= 0,01). Conclusiones: un gran porcentaje de pacientes críticos que recibe betalactámicos no alcanza las metas de PK/PD recomendadas en la actualidad

Introduction: critically ill patients have physiopathological changes that upset the concentrations of beta-lactam antibiotics. The aim was to determine if the doses of usual use in critically ill patients reach the concentrations associated with maximal activity and to establish the variables of PK/PD that are associated with suboptimal concentrations of antibiotic. Methods: prospective study conducted in an intensive therapy of adults in a period of 13 months. Patients who received cefazolin, ceftriaxone, ceftazidime or meropenem were included. Dosage of antibiotic concentration in plasma was performed at 50% of the dose interval. The concentration of free antibiotic was calculated and compared with the objective 50% fT>MIC and the objective 50% fT>MIC x 4 for susceptible microorganisms, according to CLSI criteria. The group of patients who met the 50% objective fT>MIC x 4 was compared with the one who did not, in terms of PK/PD variables. Results: 29 determinations and 55 comparisons were included. The objective 50% fT>MIC was reached in 92.7% of the cases and the target 50% fT>MIC x 4 was achieved in 61.8%. In the worst scenario, that is, considering the germ susceptible with MIC higher, only 48.3% of patients met the objective 50% fT>MIC x 4. Patients who did not reach the goal 50% fT>MIC x 4 had greater renal clearance than those who reached the goal (160 vs 108.5 ml/min/1.73m2, p=0.01). Conclusions: a large percentage of critically ill patients receiving beta-lactams do not reach the PK/PD goals recommended nowadays

Pseudomonas aeruginosa populations in the cystic fibrosis lung lose susceptibility to newly applied ß-lactams within 3 days.

BACKGROUND: Chronic pulmonary infections by Pseudomonas aeruginosa require frequent intravenous antibiotic treatment in cystic fibrosis (CF) patients. Emergence of antimicrobial resistance is common in these patients, which to date has been investigated at long-term intervals only. OBJECTIVES: To investigate under close to real-time conditions the dynamics of the response by P. aeruginosa to a single course of antibiotic therapy and the potentially associated rapid spread of antimicrobial resistance, as well as the impact on the airway microbiome. METHODS: We investigated a cohort of adult CF patients that were treated with a single course of antimicrobial combination therapy. Using daily sampling during treatment, we quantified the expression of resistance by P. aeruginosa (median of six isolates per daily sample, 347 isolates in total), measured bacterial load by P. aeruginosa-specific quantitative PCR and characterized the airway microbiome with a 16S rRNA-based approach. WGS was performed to reconstruct intrapatient strain phylogenies. RESULTS: In two patients, we found rapid and large increases in resistance to meropenem and ceftazidime. Phylogenetic reconstruction of strain relationships revealed that resistance shifts are probably due to de novo evolution and/or the selection of resistant subpopulations. We observed high interindividual variation in the reduction of bacterial load, microbiome composition and antibiotic resistance. CONCLUSIONS: We show that CF-associated P. aeruginosa populations can quickly respond to antibiotic therapy and that responses are patient specific. Thus, resistance evolution can be a direct consequence of treatment, and drug efficacy can be lost much faster than usually assumed. The consideration of these patient-specific rapid resistance shifts can help to improve treatment of CF-associated infections, for example by deeper sampling of bacteria for diagnostics, repeated monitoring of pathogen susceptibility and switching between drugs.

Dual ß-Lactam Combinations Highly Active against Mycobacterium abscessus Complex In Vitro.

As a consequence of a growing population of immunocompromised individuals, including transplant recipients and cystic fibrosis patients, there has been a dramatic increase in chronic infections caused by Mycobacterium abscessus complex (MABC) strains that are usually recalcitrant to effective antibiotic therapy. The recent rise of macrolide resistance in MABC has further complicated this clinical dilemma, dramatizing the need for novel agents. The repurposing of current antibiotics is one rapid path from discovery to patient care. In this study, we have discovered that dual ß-lactams, and specifically the combination of ceftazidime with either ceftaroline or imipenem, are synergistic and have clinically relevant activities, with MIC50s of 0.25 (ceftaroline with 100 µg/ml ceftazidime) and 0.5 µg/ml (imipenem with 100 µg/ml ceftazidime) against clinical MABC isolates. Similar synergy was observed in time-kill studies against the M. abscessus ATCC 19977 strain using clinically achievable concentrations of either imipenem (4 µg/ml) or ceftaroline (2 µg/ml), as the addition of ceftazidime at concentrations of ≥50 µg/ml showed a persistent bactericidal effect over 5 days. Treatment of THP-1 human macrophages infected with three different M. abscessus clinical isolates supported the in vitro findings, as the combination of 100 µg/ml ceftazidime and 0.125 µg/ml ceftaroline or 100 µg/ml ceftazidime and 0.25 µg/ml imipenem dramatically reduced the CFU counts to near baseline levels of infection. This study's finding that there is synergy between certain ß-lactam combinations against M. abscessus infection provides optimism toward identifying an optimum dual ß-lactam treatment regimen.IMPORTANCE The emergence of chronic MABC infections among immunocompromised populations and their inherent and acquired resistance to effective antibiotic therapy have created clinical challenges in advancing patients for transplant surgery and treating those with disease. There is an urgent need for new treatment regimens, and the repurposing of existing antibiotics provides a rapid strategy to advance a laboratory finding to patient care. Our recent discoveries that dual ß-lactams, specifically the combination of ceftazidime with ceftaroline or ceftazidime with imipenem, have significant in vitro MIC values and kill curve activities and are effective against infected THP-1 human macrophages provide optimism for a dual ß-lactam treatment strategy against MABC infections. The unexpected synergistic activities reported in this study create a new path of discovery to repurpose the large family of ß-lactam drugs.

Pharmacokinetics of Continuous Infusion Beta-lactams in the Treatment of Acute Pulmonary Exacerbations in Adult Patients With Cystic Fibrosis.

BACKGROUND: Several clinical trials have shown the efficacy of continuous infusion beta-lactam (BL) antibiotics in patients with cystic fibrosis (CF); however, little is known about pharmacokinetic changes during the treatment of an acute pulmonary exacerbation (APE). Identifying and understanding these changes may assist in optimizing antibiotic dosing during APE treatment. METHODS: This study was a retrospective cohort study of 162 adult patients with CF admitted to the University of Utah Hospital between January 1, 2008, and May 15, 2014, for treatment of an APE with both a continuous infusion BL and IV tobramycin. We extracted the administered doses of continuous infusion BLs and tobramycin along with serum drug concentrations and calculated medication clearance rates. The primary outcome was change in clearance rates of continuous infusion BLs between day 2 and day 7 of APE treatment. RESULTS: The BL clearance rate increased 20.7% (95% CI, 11.42 to 32.49; P < .001), whereas the tobramycin clearance rate decreased 6.3% (95% CI, -12.29 to -4.45; P < .001). The mean percent predicted FEV1 increased between admission and discharge by 12.2% (95% CI, -13.81 to -10.55; P < .001). CONCLUSIONS: Clinicians should monitor BL levels along with aminoglycoside levels and make dose adjustments to maximize the chance of optimal antibiotic treatment. Continuous infusion BL and tobramycin clearance can change dramatically during the treatment of an APE, which may necessitate significant changes in dosing to achieve optimal antibiotic levels. Clearance rates of these antibiotics may change in opposite directions, requiring specific monitoring of each medication.

Extended vs Bolus Infusion of Broad-Spectrum ß-Lactams for Febrile Neutropenia: An Unblinded, Randomized Trial.

Background: Febrile neutropenia may be a sign of severe infection and is associated with significant morbidity and mortality in high-risk patients with hematologic malignancies. Extended infusion of ß-lactam antibiotics is associated with greater clinical response than is bolus infusion in nonneutropenic critically ill patients, but data are lacking for febrile neutropenic patients. Methods: We designed a single-center, nonblinded, randomized trial to compare extended infusion (4 hours) and bolus infusion (30 minutes) of piperacillin-tazobactam or ceftazidime in high-risk patients with febrile neutropenia. The primary endpoint was overall response on day 4, defined as the combination of resolution of fever, sterile blood cultures, resolution of clinical signs and symptoms, and no need for a change in the antibiotic regimen. Outcome was adjudicated by investigators blinded to treatment allocation. Results: Of 123 enrolled patients, 105 had febrile neutropenia and were included in the intention-to-treat analysis: 47 in the extended infusion arm and 58 in the bolus infusion arm. Overall response occurred in 35 (74.4%) patients treated with extended infusion and 32 (55.1%) patients treated with bolus infusion (P = .044). The superiority of extended infusion was greatest for patients with clinically documented infections (overall response, 68.4% [13/19] vs 35.7% [10/28]; P = .039) and specifically for those with pneumonia (80% [4/5] vs 0% [0/8]; P = .007). Conclusions: Extended infusion of ß-lactams is associated with superior treatment outcomes compared with bolus infusion for high-risk patients with febrile neutropenia. The benefit of extended ß-lactam infusion may be greatest for patients with pulmonary infections. Clinical Trials Registration: NCT02463747.

Structure-Activity Relationship Studies of ß-Lactam-azide Analogues as Orally Active Antitumor Agents Targeting the Tubulin Colchicine Site.

We have synthesized a series of new ß-lactam-azide derivatives as orally active anti-tumor agents by targeting tubulin colchicine binding site and examined their structure activity relationship (SAR). Among them, compound 28 exhibited the most potent antiproliferative activity against MGC-803 cells with an IC50 value of 0.106 µM by induction of G2/M arrest and apoptosis and inhibition of the epithelial to mesenchymal transition. 28 acted as a novel inhibitor of tubulin polymerization by its binding to the colchicine site. SAR analysis revealed that a hydrogen atom at the C-3 position of the ß-lactam was required for the potent antiproliferative activity of ß-lactam-azide derivatives. Oral administration of compound 28 also effectively inhibited MGC-803 xenograft tumor growth in vivo in nude mice without causing significant loss of body weight. These results suggested that compound 28 is a promising orally active anticancer agent with potential for development of further clinical applications.

Modified tunicamycins with reduced eukaryotic toxicity that enhance the antibacterial activity of ß-lactams.

Tunicamycins (TUN) are inhibitors of the UDP-HexNAc: polyprenol-P HexNAc-1-P transferase family of enzymes, which initiate the biosynthesis of bacterial peptidoglycan and catalyze the first step in eukaryotic protein N-glycosylation. The TUN are therefore general and potent toxins to both eukaryotes and prokaryotes. Screening a library of synthetic TUN against Bacillus and yeast identified TUN that are antibacterial, but have significantly reduced eukaryotic toxicity. One of these (Tun-15:0) differs from the native TUN control only by the lack of the conjugated double bond in the tunicaminyl N-acyl group. Tun-15:0 also showed reduced inhibition for protein N-glycosylation in a Pichia-based bioassay. Natural TUN was subsequently modified by chemically reducing the N-acyl double bond (TunR1) or both the N-acyl and uridyl double bonds (TunR2). TunR1 and TunR2 retain their antibacterial activity, but with considerably reduced eukaryotic toxicity. In protein N-glycosylation bioassays, TunR1 is a less potent inhibitor than native TUN and TunR2 is entirely inactive. Importantly, the less toxic TunR1 and TunR2 both enhance the antibacterial activity of ß-lactams: oxacillin by 32- to 64-fold, comparable with native TUN, and with similar enhancements for methicillin and penicillin G. Hence, the modified TUNs, TunR1 and TunR2, are potentially important as less-toxic synergistic enhancers of the ß-lactams.

Clinical on-site monitoring of ß-lactam antibiotics for a personalized antibiotherapy.

An appropriate antibiotherapy is crucial for the safety and recovery of patients. Depending on the clinical conditions of patients, the required dose to effectively eradicate an infection may vary. An inadequate dosing not only reduces the efficacy of the antibiotic, but also promotes the emergence of antimicrobial resistances. Therefore, a personalized therapy is of great interest for improved patients' outcome and will reduce in long-term the prevalence of multidrug-resistances. In this context, on-site monitoring of the antibiotic blood concentration is fundamental to facilitate an individual adjustment of the antibiotherapy. Herein, we present a bioinspired approach for the bedside monitoring of free accessible ß-lactam antibiotics, including penicillins (piperacillin) and cephalosporins (cefuroxime and cefazolin) in untreated plasma samples. The introduced system combines a disposable microfluidic chip with a naturally occurring penicillin-binding protein, resulting in a high-performance platform, capable of gauging very low antibiotic concentrations (less than 6 ng ml-1) from only 1 µl of serum. The system's applicability to a personalized antibiotherapy was successfully demonstrated by monitoring the pharmacokinetics of patients, treated with ß-lactam antibiotics, undergoing surgery.

Transrectal ultrasound guided prostate biopsy in the era of increasing fluoroquinolone resistance: prophylaxis with single-dose ertapenem.

PURPOSE: The aim of the study was to compare single-dose ertapenem (ERT) with the 3-day regime of ciprofloxacin (CIP) for prophylaxis of possible infections following transrectal prostate biopsy. METHODS: Data from a consecutive group of 542 patients from January 2012 to January 2017 were retrospectively analysed. As preinterventional prophylaxis patient group A (179) received 500 mg CIP twice a day for three days, beginning on the day before the biopsy (until June 2013); group B (363) received a single dose of ERT 60 min prior to intervention. The first follow-up examination for all patients was between post-intervention days 2 and 3. The second follow-up examination was between day 15 and 30 following biopsy. Urine was cultured in all cases and any adverse drug reactions (ADRs) related to the antibiotic treatment were noted. We also recorded all clinically relevant morbidities requiring intervention (ischuria, macrohaematuria, symptomatic urinary tract infections and urosepsis), as well as those not requiring active intervention (macrohaematuria, decreased urinary stream, pain, haemospermia). The main study criterion was the symptomatic urinary tract infection rate and ADRs. RESULTS: All 542 biopsied patients could be included in the study and the drop-out rate was zero. There were no significant differences between groups A and B with regards to complications not requiring intervention. There was, however, a significant reduction from 14.5% (group A) to 0.8% (group B) in infectious complications. This showed a significant correlation in favour of ERT (p < 0.001). Furthermore, in the ERT group there was also a distinct and significant reduction (p > 0.001) in the number of patients with bacteriuria (>10e4 cfu per ml urine) without fever (0.5%) compared to the CIP group (12.3%). CONCLUSION: A single-dose of 1 g of intravenous ERT applied 1 h before a scheduled transrectal prostate biopsy is a safe option and provides effective protection against infection-related complications arising from surgery.

Acute Kidney Injury in Patients Treated with IV Beta-Lactam/Beta-Lactamase Inhibitor Combinations.

STUDY OBJECTIVE: Increased acute kidney injury (AKI) incidence has been reported in patients receiving piperacillin-tazobactam (PTZ) therapy compared with other ß-lactams. The authors sought to determine if the addition of ß-lactamase inhibitors impacts AKI incidence by comparing patients treated with PTZ or ampicillin-sulbactam (SAM). DESIGN: Retrospective cohort study. SETTING: Large academic tertiary care hospital. PATIENTS: Overall, 2448 patients received PTZ (n=1836) or SAM (n=612) for at least 48 hours between September 1, 2007, and September 30, 2015. Patients were excluded for pregnancy, cystic fibrosis, chronic kidney disease, and initial creatinine clearance < 30 ml/min. Patients were matched on Charlson Comorbidity Index, initial creatinine clearance, hypotension exposure, various nephrotoxic drug exposures, history of diabetes, heart failure, and hypertension. MEASUREMENTS AND MAIN RESULTS: AKI occurred in 265 patients at similar rates for both groups (PTZ 11.4% vs SAM 9.2%; p=0.14). After stratifying by vancomycin exposure and controlling for confounders, there was no difference in the risk of AKI for SAM or PTZ (adjusted odds ratio [aOR] 0.87, 95% confidence interval [CI] 0.59-1.25). The addition of vancomycin (VAN) to PTZ increased the likelihood of AKI compared with PTZ alone (aOR 1.77, 95% CI 1.26-2.46). Concomitant SAM and VAN therapy was not associated with a significant increase in AKI compared with SAM monotherapy (aOR 1.01, 95% CI 0.48-1.97). CONCLUSION: Rates of AKI were similar for PTZ and SAM in a matched cohort. The addition of a ß-lactamase inhibitor is not likely the mechanism in the observed increased rates of AKI in patients treated with vancomycin and PTZ.

Once-daily versus multiple-daily dosing with intravenous aminoglycosides for cystic fibrosis.

BACKGROUND: People with cystic fibrosis, who are chronically colonised with the organism Pseudomonas aeruginosa, often require multiple courses of intravenous aminoglycoside antibiotics for the management of pulmonary exacerbations. The properties of aminoglycosides suggest that they could be given in higher doses less often. This is an update of a previously published review. OBJECTIVES: To assess the effectiveness and safety of once-daily versus multiple-daily dosing of intravenous aminoglycoside antibiotics for the management of pulmonary exacerbations in cystic fibrosis. SEARCH METHODS: We searched the Cystic Fibrosis Specialist Register held at the Cochrane Cystic Fibrosis and Genetic Disorders Group's editorial base, comprising references identified from comprehensive electronic database searches, handsearching relevant journals and handsearching abstract books of conference proceedings.Date of the most recent search: 24 June 2016. SELECTION CRITERIA: All randomised controlled trials, whether published or unpublished, in which once-daily dosing of aminoglycosides has been compared with multiple-daily dosing in terms of efficacy or toxicity or both, in people with cystic fibrosis. DATA COLLECTION AND ANALYSIS: The two authors independently selected the studies to be included in the review and assessed the risk of bias of each study; authors also assessed the quality of the evidence using the GRADE criteria. Data were independently extracted by each author. Authors of the included studies were contacted for further information. As yet unpublished data were obtained for one of the included studies. MAIN RESULTS: Fifteen studies were identified for possible inclusion in the review. Four studies reporting results from a total of 328 participants (aged 5 to 50 years) were included in this review. All studies compared once-daily dosing with thrice-daily dosing. One study had a low risk of bias for all criteria assessed; the remaining three included studies had a high risk of bias from blinding, but for other criteria were judged to have either an unclear or a low risk of bias.There was no significant difference between treatment groups in: forced expiratory volume in one second, mean difference 0.33 (95% confidence interval -2.81 to 3.48, moderate quality evidence); forced vital capacity, mean difference 0.29 (95% confidence interval -6.58 to 7.16, low quality evidence); % weight for height, mean difference -0.82 (95% confidence interval -3.77 to 2.13, low quality evidence); body mass index, mean difference 0.00 (95% confidence interval -0.42 to 0.42, low quality evidence); or in the incidence of ototoxicity, relative risk 0.56 (95% confidence interval 0.04 to 7.96, moderate quality evidence). The percentage change in creatinine significantly favoured once-daily treatment in children, mean difference -8.20 (95% confidence interval -15.32 to -1.08, moderate quality evidence), but showed no difference in adults, mean difference 3.25 (95% confidence interval -1.82 to 8.33, moderate quality evidence). The included trials did not report antibiotic resistance patterns or quality of life. AUTHORS' CONCLUSIONS: Once- and three-times daily aminoglycoside antibiotics appear to be equally effective in the treatment of pulmonary exacerbations of cystic fibrosis. There is evidence of less nephrotoxicity in children.

Antibiotics-First Versus Surgery for Appendicitis: A US Pilot Randomized Controlled Trial Allowing Outpatient Antibiotic Management.

STUDY OBJECTIVE: Randomized trials suggest that nonoperative treatment of uncomplicated appendicitis with antibiotics-first is safe. No trial has evaluated outpatient treatment and no US randomized trial has been conducted, to our knowledge. This pilot study assessed feasibility of a multicenter US study comparing antibiotics-first, including outpatient management, with appendectomy. METHODS: Patients aged 5 years or older with uncomplicated appendicitis at 1 US hospital were randomized to appendectomy or intravenous ertapenem greater than or equal to 48 hours and oral cefdinir and metronidazole. Stable antibiotics-first-treated participants older than 13 years could be discharged after greater than or equal to 6-hour emergency department (ED) observation with next-day follow-up. Outcomes included 1-month major complication rate (primary) and hospital duration, pain, disability, quality of life, and hospital charges, and antibiotics-first appendectomy rate. RESULTS: Of 48 eligible patients, 30 (62.5%) consented, of whom 16 (53.3%) were randomized to antibiotics-first and 14 (46.7%) to appendectomy. Median age was 33 years (range 9 to 73 years), median WBC count was 15,000/µL (range 6,200 to 23,100/µL), and median computed tomography appendiceal diameter was 10 mm (range 7 to 18 mm). Of 15 antibiotic-treated adults, 14 (93.3%) were discharged from the ED and all had symptom resolution. At 1 month, major complications occurred in 2 appendectomy participants (14.3%; 95% confidence interval [CI] 1.8% to 42.8%) and 1 antibiotics-first participant (6.3%; 95% CI 0.2% to 30.2%). Antibiotics-first participants had less total hospital time than appendectomy participants, 16.2 versus 42.1 hours, respectively. Antibiotics-first-treated participants had less pain and disability. During median 12-month follow-up, 2 of 15 antibiotics-first-treated participants (13.3%; 95% CI 3.7% to 37.9%) developed appendicitis and 1 was treated successfully with antibiotics; 1 had appendectomy. No more major complications occurred in either group. CONCLUSION: A multicenter US trial comparing antibiotics-first to appendectomy, including outpatient management, is feasible to evaluate efficacy and safety.

High target attainment for ß-lactam antibiotics in intensive care unit patients when actual minimum inhibitory concentrations are applied.

Patients in the intensive care unit (ICU) are at risk for suboptimal levels of ß-lactam antibiotics, possibly leading to poor efficacy. Our aim was to investigate whether the actual minimum inhibitory concentration (MIC) compared to the more commonly used arbitrary epidemiological cut-off values (ECOFFs) would affect target attainment in ICU patients on empirical treatment with broad-spectrum ß-lactam antibiotics and to identify risk factors for not reaching target. In a prospective, multicenter study, ICU patients ≥18 years old and treated with piperacillin/tazobactam, meropenem, or cefotaxime were included. Clinical and laboratory data were recorded. Serum trough antibiotic levels from three consecutive days were analyzed by liquid chromatography-mass spectrometry (LC-MS). The target was defined as the free trough concentration above the MIC (100% fT>MIC). MICECOFF was used as the target and, when available, the actual MIC (MICACTUAL) was applied. The median age of the patients was 70 years old, 52% (58/111) were males, and the median estimated glomerular filtration rate (eGFR) was 48.0 mL/min/1.73 m2. The rate of patients reaching 100% fT > MICACTUAL was higher (89%, 31/35) compared to the same patients using MICECOFF (60%, p = 0.002). In total, 55% (61/111) reached 100% fT > MICECOFF. Increased renal clearance was independently associated to not reaching 100% fT > MICECOFF. On repeated sampling, >77% of patients had stable serum drug levels around the MICECOFF. Serum concentrations of ß-lactam antibiotics vary extensively between ICU patients. The rate of patients not reaching target was markedly lower for the actual MIC than when the arbitrary MIC based on the ECOFF was used, which is important to consider in future studies.