scholarly journals Carbapenem-Resistant Gram-Negative Bacterial Infections in Children

2019 ◽  
Vol 64 (3) ◽  
Author(s):  
David Aguilera-Alonso ◽  
Luis Escosa-García ◽  
Jesús Saavedra-Lozano ◽  
Emilia Cercenado ◽  
Fernando Baquero-Artigao

ABSTRACT Carbapenem-resistant organisms (CRO) are a major global public health threat. Enterobacterales hydrolyze almost all β-lactams through carbapenemase production. Infections caused by CRO are challenging to treat due to the limited number of antimicrobial options. This leads to significant morbidity and mortality. Over the last few years, several new antibiotics effective against CRO have been approved. Some of them (e.g., plazomicin or imipenem-cilastatin-relebactam) are currently approved for use only by adults; others (e.g., ceftazidime-avibactam) have recently been approved for use by children. Recommendations for antibiotic therapy of CRO infections in pediatric patients are based on evidence mainly from adult studies. The availability of pediatric pharmacokinetic and safety data is the cornerstone to broaden the use of proposed agents in adults to the pediatric population. This article provides a comprehensive review of the current knowledge regarding infections caused by CRO with a focus on children, which includes epidemiology, risk factors, outcomes, and antimicrobial therapy management, with particular attention being given to new antibiotics.

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S684-S684
Author(s):  
Victoria Konold ◽  
Palak Bhagat ◽  
Jennifer Pisano ◽  
Natasha N Pettit ◽  
Anish Choksi ◽  
...  

Abstract Background To meet the core elements required for antimicrobial stewardship programs, our institution implemented a pharmacy-led antibiotic timeout (ATO) process in 2017 and a multidisciplinary ATO process in 2019. An antibiotic timeout is a discussion and review of the need for ongoing empirical antibiotics 2-4 days after initiation. This study sought to evaluate both the multidisciplinary ATO and the pharmacy-led ATO in a pediatric population, compare the impact of each intervention on antibiotic days of therapy (DOT) to a pre-intervention group without an ATO, and to then compare the impact of the pharmacy-led ATO versus multidisciplinary ATO on antibiotic days of therapy (DOT). Methods This was a retrospective, pre-post, quasi-experimental study of pediatric patients comparing antibiotic DOT prior to ATO implementation (pre-ATO), during the pharmacy-led ATO (pharm-ATO), and during the multidisciplinary ATO (multi-ATO). The pre-ATO group was a patient sample from February-September 2016, prior to the initiation of a formal ATO. The pharmacy-led ATO was implemented from February-September 2018. This was followed by a multidisciplinary ATO led by pediatric residents and nurses from February-September 2019. Both the pharm-ATO and the multi-ATO were implemented as an active non-interruptive alert added to the electronic health record patient list. This alert triggered when new antibiotics had been administered to the patient for 48 hours, at which time, the responsible clinician would discuss the antibiotic and document their decision via the alert workspace. Pediatric patients receiving IV or PO antibiotics administered for at least 48 hours were included. The primary outcome was DOT. Secondary outcomes included length of stay (LOS) and mortality. Results 1284 unique antibiotic orders (n= 572 patients) were reviewed in the pre-ATO group, 868 (n= 323 patients) in the pharm-ATO and 949 (n= 305 patients) in the multi-ATO groups. Average DOT was not significantly different pre vs post intervention for either methodology (Table 1). Mortality was similar between groups, but LOS was longer for both intervention groups (Table 1). Impact of an ATO on DOT, Mortality and LOS Conclusion An ATO had no impact on average antibiotic DOT in a pediatric population, regardless of the ATO methodology. Disclosures All Authors: No reported disclosures


2020 ◽  
Vol 12 (9) ◽  
pp. 893-896 ◽  
Author(s):  
Visish M Srinivasan ◽  
Caroline C Hadley ◽  
Marc Prablek ◽  
Melissa LoPresti ◽  
Stephanie H Chen ◽  
...  

BackgroundDiagnostic cerebral angiograms are increasingly being performed by transradial access (TRA) in adults, following data from the coronary literature supporting fewer access-site complications. Despite this ongoing trend in neuroangiography, there has been no discussion of its use in the pediatric population. Pediatric TRA has scarcely been described even for coronary or other applications. This is the first dedicated large study of transradial access for neuroangiography in pediatric patients.MethodsA multi-institutional series of consecutively performed pediatric transradial angiograms and interventions was collected. This included demographic, procedural, outcomes, and safety data. Data was prospectively recorded and retrospectively analyzed.ResultsThirty-seven diagnostic angiograms and 24 interventions were performed in 47 pediatric patients. Mean age, height, and weight was 14.1 years, 158.6 cm, and 57.1 kg, respectively. The radial artery measured 2.09+/-0.54 mm distally, and 2.09+/-0.44 mm proximally. Proximal and distal angiography were performed for both diagnostic and interventional application (17 distal angiograms, two distal interventions). Clinically significant vasospasm occurred in eight patients (13.1%). Re-access was successfully performed 11 times in seven patients. Conversion to femoral access occurred in five cases (8.2%). The only access-related complication was a small asymptomatic wrist hematoma after TR band removal.ConclusionsTransradial access in pediatric patients is safe and feasible. It can be performed successfully in many cases but carries some unique challenges compared with the adult population. Despite the challenge of higher rates of vasospasm and conversion to femoral access, it is worth exploring further, given the potential benefits.


2021 ◽  
Author(s):  
Viivi Hirvonen ◽  
Tal Moshe Weizmann ◽  
Adrian Mulholland ◽  
James Spencer ◽  
Marc van der Kamp

OXA-48 β-lactamases are frequently encountered in bacterial infections caused by carbapenem-resistant Gram-negative bacteria. Due to the importance of carbapenems in treatment of healthcare-associated infections, and the increasingly wide dissemination of OXA-48-like enzymes on plasmids, these β-lactamases are of high clinical significance. Notably, OXA-48 hydrolyses imipenem more efficiently than other commonly used carbapenems, such as meropenem. Here, we use extensive multi-scale simulations of imipenem and meropenem hydrolysis by OXA-48 to dissect the dynamics and to explore differences in reactivity of the possible conformational substates of the respective acylenzymes. QM/MM simulations of the deacylation reaction for both substrates demonstrate that deacylation is favoured when the 6α-hydroxyethyl group is able to hydrogen bond to the water molecule responsible for deacylation, but disfavoured by increasing hydration of either oxygen of the carboxylated Lys73 general base. Differences in free energy barriers calculated from the QM/MM simulations correlate well with the experimentally observed differences in hydrolytic efficiency between meropenem and imipenem. We conclude that the impaired breakdown of meropenem, compared to imipenem, which arises from a subtle change in the hydrogen bonding pattern between the deacylating water molecule and the antibiotic, is most likely induced by the meropenem 1-methyl group. In addition to increased insights into carbapenem breakdown by OXA β-lactamases, which may aid design of new antibiotics or inhibitors, our approach exemplifies the combined use of atomistic simulations in determining the possible different enzyme-substrate substates, and their influence on enzyme reaction kinetics.


2014 ◽  
Vol 14 (5) ◽  
pp. 508-513 ◽  
Author(s):  
Alan A. Moazzam ◽  
Ernest Nehrer ◽  
Stephanie L. Da Silva ◽  
José C. Polido ◽  
Anush Arakelyan ◽  
...  

Object Cerebrospinal fluid–diverting shunts are often complicated by bacterial infections. Dental procedures are known to cause transient bacteremia that could potentially spread hematogenously to these implanted devices. No literature currently exists to inform practitioners as to the need for prophylactic antibiotics for patients who possess these implants. The authors performed a retrospective study to assess whether dental procedures and poor oral health were associated with a higher likelihood of developing CSF-diverting shunt infections. Methods Neurosurgical and pediatric dental records from January 2007 to December 2012 were reviewed for shunt surgeries and dental encounters. Indications for shunt surgery and infection rates were recorded. Dental records were reviewed for several markers of overall dental health, such as a DMFT (decayed, missing, and filled teeth) score and a gingival health/oral hygiene score. The association between these scores and the incidence of shunt infections were studied. Moreover, the relationship between the incidence of shunt infections and the timing and invasiveness of preceding dental encounters were analyzed. Results A total of 100 pediatric patients were included in our study, for a total of 204 shunt surgeries. Twenty-one shunt infections were noted during the 6-year study period. Five of these shunts infections occurred within 3 months of a dental procedure. The odds ratio (OR) of developing a shunt infection within 3 months of a dental procedure was 0.98 (95% confidence interval [CI] 0.27–3.01), and was not statistically significant. The OR of developing a shunt infection after a high-risk dental procedure compared with a low-risk dental procedure was 1.32 (95% CI 0.02–16.29), and was not statistically significant. There was no significant association between measures of dental health, such as DMFT and gingival health score, and the likelihood of developing a shunt infection. The ORs for these 2 scores were 0.51 (95% CI 0.04–4.96) and 1.58 (95% CI 0.03–20.06), respectively. The study was limited by sample size. Conclusions Dental health status and the number and type of dental procedures performed do not appear to confer a higher risk of developing a CSF-diverting shunt infection in this pediatric population.


2018 ◽  
Vol 85 (3) ◽  
Author(s):  
Anou M. Somboro ◽  
Daniel G. Amoako ◽  
John Osei Sekyere ◽  
Hezekiel M. Kumalo ◽  
René Khan ◽  
...  

ABSTRACT Metallo-β-lactamase (MBL)-producing Enterobacteriaceae are of grave clinical concern, particularly as there are no metallo-β-lactamase inhibitors approved for clinical use. The discovery and development of MBL inhibitors to restore the efficacy of available β-lactams are thus imperative. We investigated a zinc-chelating moiety, 1,4,7-triazacyclononane (TACN), for its inhibitory activity against clinical carbapenem-resistant Enterobacteriaceae. MICs, minimum bactericidal concentrations (MBCs), the serum effect, fractional inhibitory concentration indexes, and time-kill kinetics were determined using broth microdilution techniques according to Clinical and Laboratory Standards Institute (CSLI) guidelines. Enzyme kinetic parameters and the cytotoxic effects of TACN were determined using spectrophotometric assays. The interactions of the enzyme-TACN complex were investigated by computational studies. Meropenem regained its activity against carbapenemase-producing Enterobacteriaceae, with the MIC decreasing from between 8 and 64 mg/liter to 0.03 mg/liter in the presence of TACN. The TACN-meropenem combination showed bactericidal effects with an MBC/MIC ratio of ≤4, and synergistic activity was observed. Human serum effects on the MICs were insignificant, and TACN was found to be noncytotoxic at concentrations above the MIC values. Computational studies predicted that TACN inhibits MBLs by targeting their catalytic active-site pockets. This was supported by its inhibition constant (Ki), which was 0.044 μM, and its inactivation constant (Kinact), which was 0.0406 min−1, demonstrating that TACN inhibits MBLs efficiently and holds promise as a potential inhibitor. IMPORTANCE Carbapenem-resistant Enterobacteriaceae (CRE)-mediated infections remain a significant public health concern and have been reported to be critical in the World Health Organization’s priority pathogens list for the research and development of new antibiotics. CRE produce enzymes, such as metallo-β-lactamases (MBLs), which inactivate β-lactam antibiotics. Combination therapies involving a β-lactam antibiotic and a β-lactamase inhibitor remain a major treatment option for infections caused by β-lactamase-producing organisms. Currently, no MBL inhibitor–β-lactam combination therapy is clinically available for MBL-positive bacterial infections. Hence, developing efficient molecules capable of inhibiting these enzymes could be a promising way to overcome this phenomenon. TACN played a significant role in the inhibitory activity of the tested molecules against CREs by potentiating the activity of carbapenem. This study demonstrates that TACN inhibits MBLs efficiently and holds promises as a potential MBL inhibitor to help curb the global health threat posed by MBL-producing CREs.


Author(s):  
Alain Lepape ◽  
Astrid Jean ◽  
Jan De Waele ◽  
Arnaud Friggeri ◽  
Anne Savey ◽  
...  

Abstract Background Antimicrobial resistance (AMR) compromises the treatment of patients with serious infections in intensive care units (ICUs), and intensive care physicians are increasingly facing patients with bacterial infections with limited or no adequate therapeutic options. A survey was conducted to assess the intensive care physicians’ perception of the AMR situation in the European Union/European Economic Area (EU/EEA). Methods Between May and July 2017, physicians working in European ICUs were invited to complete an online questionnaire hosted by the European Society of Intensive Care Medicine. The survey included 20 questions on hospital and ICU characteristics, frequency of infections with multidrug-resistant (MDR) bacteria and relevance of AMR in the respondent’s ICU, management of antimicrobial treatment as well as the use of last-line antibiotics in the six months preceding the survey. For the analysis of regional differences, EU/EEA countries were grouped into the four sub-regions of Eastern, Northern, Southern and Western Europe. Results Overall, 1062 responses from four European sub-regions were analysed. Infections with MDR bacteria in their ICU were rated as a major problem by 257 (24.2%), moderate problem by 360 (33.9%) and minor problem by 391 (36.8%) respondents. Third-generation cephalosporin-resistant Enterobacteriaceae were the most frequently encountered MDR bacteria followed by, in order of decreasing frequency, meticillin-resistant Staphylococcus aureus, carbapenem-resistant Enterobacteriaceae, carbapenem-resistant Pseudomonas aeruginosa and vancomycin-resistant enterococci. Perception of the relevance of the AMR problem and the frequency of specific MDR bacteria varied by European sub-region. Bacteria resistant to all or almost all available antibiotics were encountered by 132 (12.4%) respondents. Many physicians reported not having access to specific last-line antibiotics. Conclusions The percentage of European ICU physicians perceiving AMR as a substantial problem in their ICU is high with variation by sub-region in line with epidemiological studies. The reports of bacteria resistant to almost all available antibiotics and the limited availability of last-line antibiotics in ICUs in the EU/EEA are of concern.


2020 ◽  
Vol 30 (6) ◽  
Author(s):  
Maryam Moradian ◽  
Batool Hejazi Zadeh ◽  
Fariba Rashidi Ghader ◽  
Mohammad Rafie Khorgami ◽  
Kambiz Mozaffari ◽  
...  

Background: Cardiac neoplasms are not common in the pediatric population, and most of the reported cases in the literature are benign. Despite their benign nature, however, cardiac neoplasms may lead to hemodynamic instability and arrhythmias. Objectives: Our study aimed to review the natural history, diagnosis, pathological features, and outcome of pediatric patients with cardiac tumors presenting to a tertiary pediatric cardiac center over an 8-year period. Methods: This retrospective observational study reviewed and analyzed the hospital records and data of pediatric patients diagnosed with cardiac tumors over an 8-year period (2007 - 2015). Results: During the period covered by the study (2007 - 2015), a total of 62975 pediatric in and out patients were referred to our tertiary cardiac center for cardiac evaluation. Cardiac tumors were identified in 41 patients, in 35 of whom tumor types were recognized. Rhabdomyomas were the most common tumors, followed by fibromas and myxomas. Fourteen patients underwent surgical management (either total or partial resection), and 4 patients received chemotherapy. Associated congenital heart diseases, except for the patent foramen ovale, were detected in12 patients. Conclusions: While almost all our findings were compatible with previous data, we had a comparatively large number of undetermined tumors. Therefore, a better understanding of the imaging characteristics of cardiac tumors is needed for a better diagnosis of tumor types via noninvasive modalities.


2021 ◽  
Author(s):  
Matthew Mitcheltree ◽  
Amarnath Pisipati ◽  
Egor A. Syroegin ◽  
Katherine J. Silvestre ◽  
Dorota Klepacki ◽  
...  

The dearth of new medicines effective against antibiotic-resistant bacteria presents a growing global public health concern. For more than five decades, the search for new antibiotics has relied heavily upon the chemical modification of natural products (semi-synthesis), a method ill-equipped to combat rapidly evolving resistance threats. Semi-synthetic modifications are typically of limited scope within polyfunctional antibiotics, usually increase molecular weight, and seldom permit modifications of the underlying scaffold. When properly designed, fully synthetic routes can easily address these shortcomings. Here we report the structure-guided design and component-based synthesis of a rigid oxepanoproline scaffold which, when linked to the aminooctose residue of clindamycin, produces an antibiotic of exceptional potency and spectrum of activity, here named iboxamycin. Iboxamycin is effective in strains expressing Erm and Cfr rRNA methyltransferase enzymes, products of genes that confer resistance to all clinically relevant antibiotics targeting the large ribosomal subunit, namely macrolides, lincosamides, phenicols, oxazolidinones, pleuromutilins, and streptogramins. X-ray crystallographic studies of iboxamycin in complex with the native 70S bacterial ribosome, as well as the Erm-methylated 70S ribosome, uncover the structural basis for this enhanced activity, including an unforeseen and unprecedented displacement of upon antibiotic binding. In mice, iboxamycin is orally bioavailable, safe, and effective in treating bacterial infections, testifying to the capacity for chemical synthesis to provide new antibiotics in an era of rising resistance.


2021 ◽  
Vol 12 ◽  
Author(s):  
Elzbieta Moszczyńska ◽  
Elzbieta Marczak ◽  
Mieczysław Szalecki ◽  
Krzysztof Kądziołka ◽  
Marcin Roszkowski ◽  
...  

BackgroundThis study aims to analyze the diagnostic accuracy of bilateral inferior petrosal sinus sampling (BIPSS), the gold standard test for the differential diagnosis of ACTH-dependent Cushing’s syndrome (CS) in a group of pediatric patients with Cushing’s disease (CD).MethodsThis is a retrospective analysis which include 12 patients with hypercortisolemia and inconclusive pituitary MRI, who underwent bilateral inferior petrosal sinus sampling (BIPSS) and transsphenoidal surgery (TSS) from 2004 to 2020 in the Children’s Memorial Health Institute (CMHI) Warsaw, Poland. Pituitary origin of ACTH secretion was considered if baseline central to peripheral (C/P) ACTH level ratio was ≥ 2 or C/P ratio was ≥ 3 after human corticotropin-releasing hormone (hCRH) stimulation. The diagnosis was histologically confirmed in almost all cases after TSS.ResultsThe diagnostic accuracy of BIPSS reached 75% at baseline and 83.3% after CRH stimulation. The compatibility of localization of a microadenoma by BIPSS with the surgical location was 66.7%.ConclusionsOwing to its high diagnostic effectiveness, BIPSS remains the best test to differentiate CD from EAS. The indications for the procedure should be carefully considered, because EAS in the pediatric population, unlike in adults, is extremely rare. Moreover BIPSS has only limited value for indicating tumor localization.


2021 ◽  
pp. 120347542110497
Author(s):  
Muskaan Sachdeva ◽  
Patrick Kim ◽  
Asfandyar Mufti ◽  
Khalad Maliyar ◽  
Cathryn Sibbald ◽  
...  

Background: There is currently at least 1 biologic (adalimumab) approved in North America for treatment of Hidradenitis Suppurativa in the pediatric population. However, no reviews or clinical trials have specifically analyzed the effectiveness and safety data of biologic use in this population. The objective of this systematic review is to identify and summarize the outcomes of biologic therapy in pediatric patients with HS. Methods: MEDLINE and EMBASE databases were used to conduct the search on Sept 18, 2020. Results: The 15 included studies consisted of 26 patients, with the mean age of 15 ± 2.3 years. Females accounted for 53.8% ( n = 14/26) of cases. The mean duration of HS prior to biologic initiation was 3.5 ± 2.9 years, with the majority having Hurley Stage II. The 26 patients received 34 biologics in total: 85.3% treated with TNF alpha inhibitors (adalimumab n = 17, infliximab n = 10, etanercept n = 1, unspecified n = 1), 5.9% with IL-12/23 inhibitors (ustekinumab n = 2), 5.9% with IL-1 inhibitors (i.e., anakinra n = 2) and 2.9% received IL-23 inhibitors (i.e., guselkumab n = 1) biologics. Of the 26 patients, 23.1% ( n = 6/26) experienced complete resolution (CR), 73.1% ( n = 19/26) experienced partial resolution (PR), and 3.8% ( n = 1/26) had no resolution outcomes reported. The time to resolution of HS lesions after biologic initiation ranged from 10 days to 11.5 months (mean: 5.1 months). No adverse events were reported in the studies. Conclusion: Although anti-TNF alpha were the most common biologics used for HS in pediatric cases, large-scale trials specific to pediatric patients with HS are needed to confirm these findings.


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