Broad-spectrum Beta-lactam Antibiotics Research Articles

The “toxic window” of amoxicillin exposure during pregnancy on long bone development in fetal mice

AimsAmoxicillin is a broad-spectrum beta-lactam antibiotic used to treat infectious diseases in pregnant women. Studies have shown that prenatal amoxicillin exposure (PAmE) has developmental toxicity on fetal development. However, the effect of PAmE on long bone development has not been reported. This study aimed to investigate the “toxic window” of PAmE on long bone development and explore its possible mechanism in fetal mice. Materials and methodsPregnant mice were administered amoxicillin by gavage at different stages (gestational day (GD)10–12 and GD16–18), different doses (150 and 300 mg/kg·d) and different courses (single and multiple courses). Fetal femurs were collected at GD18 and bone development related indicators were detected. Key findingsThe results showed that PAmE significantly reduced the length of the femur and primary ossification center of fetal mice, and inhibited the development of fetal growth plate. Meanwhile, PAmE inhibited the development of bone marrow mesenchymal stem cells, osteoclasts and endothelial cells in fetal long bone. Further, we found the fetal long bone developmental toxicity induced by PAmE was most significant at late-pregnancy (GD16–18), high dose (300 mg/kg·d) and multiple-course group. Besides, PAmE inhibited the expression of Wnt/β-catenin signaling pathway in fetal long bone. The β-catenin mRNA expression was significantly positively correlated with the development indexes of fetal long bone. SignificancePAmE has toxic effects on long bone development, and there was an obvious “toxic window” of PAmE on the long bone development in fetal mice. The Wnt/β-catenin signaling pathway may mediate PAmE-induced fetal long bone development inhibition.

Which Are the Best Regimens of Broad-Spectrum Beta-Lactam Antibiotics in Burn Patients? A Systematic Review of Evidence from Pharmacology Studies.

Burn injury causes profound pathophysiological changes in the pharmacokinetic/pharmacodynamic (PK/PD) properties of antibiotics. Infections are among the principal complications after burn injuries, and broad-spectrum beta-lactams are the cornerstone of treatment. The aim of this study was to review the evidence for the best regimens of these antibiotics in the burn patient population. We performed a systematic review of evidence available on MEDLINE (from its inception to 2023) of pharmacology studies that focused on the use of 13 broad-spectrum beta-lactams in burn patients. We extracted and synthetized data on drug regimens and their ability to attain adequate PK/PD targets. We selected 35 studies for analysis. Overall, studies showed that both high doses and the continuous infusion (CI) of broad-spectrum beta-lactams were needed to achieve internationally-recognized PK/PD targets, ideally with therapeutic drug monitoring guidance. The most extensive evidence concerned meropenem, but similar conclusions could be drawn about piperacillin-tazobactam, ceftazidime, cefepime, imipenem-clinastatin and aztreonam. Insufficient data were available about new beta-lactam-beta-lactamase inhibitor combinations, ceftaroline, ceftobiprole and cefiderocol. Both high doses and CI of broad-spectrum beta-lactams are needed when treating burn patients due to the peculiar changes in the PK/PD of antibiotics in this population. Further studies are needed, particularly about newer antibiotics.

Stability Studies of Antipseudomonal Beta Lactam Agents for Outpatient Therapy.

Outpatient parenteral antimicrobial therapy (OPAT) is a useful treatment strategy against Pseudomonas aeruginosa and other multidrug-resistant bacteria. However, it is hindered by the lack of stability data for the administration of antibiotics under OPAT conditions. Our objective was to investigate the stability of nine antipseudomonal and broad-spectrum beta lactam antibiotics (aztreonam, cefepime, cefiderocol, ceftazidime, ceftazidime/avibactam, ceftolozane/tazobactam, meropenem, meropenem/vaborbactam, and piperacillin/tazobactam) to allow the spread of OPAT programs. All the antibiotics were diluted in 500 mL 0.9% sodium chloride and stored at 4, 25, 32, and 37 °C for 72 h in two different devices (infusion bags and elastomeric pumps). The solutions were considered stable if the color, clearness, and pH remained unchanged and if the percentage of intact drug was ≥90%. All the antimicrobials remained stable 72 h under refrigerated conditions and at least 30 h at 25 °C. At 32 °C, all the antibiotics except for meropenem and meropenem/vaborbactam remained stable for 24 h or more. At 37 °C, only aztreonam, piperacillin/tazobactam, cefepime, cefiderocol, and ceftolozane/tazobactam were stable for at least 24 h. The stability results were the same in the two devices tested. All the antibiotics studied are actual alternatives for the treatment of antipseudomonal or multidrug-resistant infections in OPAT programs, although the temperature of the devices is crucial to ensure antibiotic stability.

Faecal Carriage of Amp C Producing E. coli and Klebsiella Spp

Amp C-producing organisms can act as a hidden reservoir for ESBLs; the high-level expression of the Amp C β-lactamases may mask the recognition of the ESBLs. In recent years, the world has seen a surge in Enterobacteriaceae resistant to broad-spectrum beta-lactam antibiotics due to the production of Extended-Spectrum Beta-Lactamases (ESBLs) or Plasmid-mediated Amp C (pAmp C) enzymes

Monooxygenases and Antibiotic Resistance: A Focus on Carbapenems.

Carbapenems are a group of broad-spectrum beta-lactam antibiotics that in many cases are the last effective defense against infections caused by multidrug-resistant bacteria, such as some strains of Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii. Resistance to carbapenems has emerged and is beginning to spread, becoming an ongoing public-health problem of global dimensions, causing serious outbreaks, and dramatically limiting treatment options. This paper reviews the role of flavin monooxygenases in antibiotic resistance, with a specific focus on carbapenem resistance and the recently discovered mechanism mediated by Baeyer-Villiger monooxygenases. Flavin monooxygenases are enzymes involved in the metabolism and detoxification of compounds, including antibiotics. Understanding their role in antibiotic resistance is crucial. Carbapenems are powerful antibiotics used to treat severe infections caused by multidrug-resistant bacteria. However, the rise of carbapenem-resistant strains poses a significant challenge. This paper explores the mechanisms by which flavin monooxygenases confer resistance to carbapenems, examining molecular pathways and genetic factors. Additionally, this paper highlights the discovery of Baeyer-Villiger monooxygenases' involvement in antibiotic resistance. These enzymes catalyze the insertion of oxygen atoms into specific chemical bonds. Recent studies have revealed their unexpected role in promoting carbapenem resistance. Through a comprehensive analysis of the literature, this paper contributes to the understanding of the interplay between flavin monooxygenases, carbapenem resistance, and Baeyer-Villiger monooxygenases. By exploring these mechanisms, it aims to inform the development of strategies to combat antibiotic resistance, a critical global health concern.

Antibiotic Susceptibility Patterns for Carbapenem-Resistant Enterobacteriaceae.

Carbapenem is a broad-spectrum beta-lactam antibiotic considered the last choice for the treatment of antibiotic-resistant Gram-negative bacteria. Thus, the increasing rate of carbapenem resistance (CR) in Enterobacteriaceae is an urgent public health threat. This study aimed to evaluate the antibiotic susceptibility pattern of carbapenem-resistant Enterobacteriaceae (CRE) to new and old antibiotics. In this study, Klebsiella pneumoniae, E. coli, and Enterobacter spp. were collected from 10 hospitals in Iran for one year. CRE is recognized by resistance to meropenem and/or imipenem disk after identification of the collected bacteria. Antibiotic susceptibility of CRE against fosfomycin, rifampin, metronidazole, tigecycline, and aztreonam was detected by disk diffusion method and colistin by MIC. In this study, 1222 E. coli, 696 K. pneumoniae, and 621 Enterobacter spp. were collected from 10 hospitals in Iran in one year. Fifty-four E. coli (4.4%), 84 K. pneumoniae (12%), and 51 Enterobacter spp. (8.2%) were CRE. All CRE strains were resistant to metronidazole and rifampicin. Tigecycline has the highest sensitivity on CRE and levofloxacin for Enterobacter spp. Tigecycline showed an acceptable effectiveness rate of sensitivity on the CRE strain. Therefore, we suggest that clinicians consider this valuable antibiotic to treat CRE.

Fate of Horizontal-Gene-Transfer Markers and Beta-Lactamase Genes during Thermophilic Composting of Human Excreta

Thermophilic composting is a suitable treatment for the recycling of organic wastes for agriculture. However, using human excreta as feedstock for composting raises concerns about antibiotic resistances. We analyzed samples from the start and end of a thermophilic composting trial of human excreta, together with green cuttings and straw, with and without biochar. Beta-lactamase genes blaCTX-M, blaIMP, and blaTEM conferring resistance to broad-spectrum beta-lactam antibiotics, as well as horizontal gene transfer marker genes, intI1 and korB, were quantified using qPCR. We found low concentrations of the beta-lactamase genes in all samples, with non-significant mean decreases in blaCTX-M and blaTEM copy numbers and a mean increase in blaIMP copy numbers. The decrease in both intI1 and korB genes from start to end of composting indicated that thermophilic composting can decrease the horizontal spread of resistance genes. Thus, thermophilic composting can be a suitable treatment for the recycling of human excreta.

949. Risk Factors for Subsequent Multidrug-Resistant Gram-Negative Bloodstream Infection Following an Initial Gram-Negative Bloodstream Infection among Solid Organ Transplant Recipients

Abstract Background Multidrug-resistant (MDR) Gram-negative (GN) bloodstream infections (BSI) are a major cause of morbidity and mortality among solid organ transplant recipients (SOTR). We determined risk factors associated with subsequent MDR-GN BSI following an initial Enterobacterales (EB) BSI among SOTRs. Methods A retrospective cohort study was performed. All SOTR with an EB BSI at the Hospital of the University of Pennsylvania and University of Maryland Medical Center between 1 Jan 2007 and 30 June 2018 and The Johns Hopkins Hospital between 1 Jan 2005 and 31 Dec 2015 were included. The primary outcome was any MDR-GN BSI within 60 days of the EB BSI, including MDR-EB (defined by ceftriaxone MIC ≥8μg/mL), and MDR-Pseudomonas and Acinetobacter (defined by resistance to three or more antibiotic classes). Unadjusted analyses were performed to identify possible risk factors, using a Fisher’s exact or χ 2 test for categorical and Student’s t-test for continuous variables. Results Of 988 SOTR with an EB BSI, 138 (14%) had a MDR-GN BSI within 60 days. In unadjusted analyses, possible risk factors for a subsequent MDR-GN BSI (Table 1) included: (1) an index BSI due to extended-spectrum beta-lactamase (ESBL)-producing EB (compared to a susceptible index EB BSI); (2) a carbapenem-resistant EB (CRE) index BSI (compared to a susceptible index EB BSI); (3) exposure to piperacillin-tazobactam or carbapenems in the 6 months prior to the index EB BSI; (4) prior liver transplantation; and (5) need for reoperation within four weeks of the original transplantation. There was no significant association between recurrent MDR-GN BSI and immunosuppression at time of infection, induction immunosuppression history, acute rejection history, or primary graft dysfunction. Table 1. Risk factors for subsequent MDR-GN BSI following EB BSI among SOTR. Data are presented as numbers (percentages) except where noted. Abbreviations: BSI, bloodstream infection; CRE, carbapenem-resistant Enterobacterales; EB, Enterobacterales; ESBL, extended-spectrum beta-lactamase; GN, Gram-negative; IQR, interquartile range; MDR, multidrug-resistant Conclusion This study shows that liver transplantation, reoperation following transplantation, an index ESBL-EB or CRE BSI, and recent exposure to broad-spectrum beta-lactam antibiotics are associated with an increased odds of subsequent MDR-GN BSI in SOTR, and underscores the need for future studies aimed at preventing emergence of MDR-GN infections in this vulnerable population. Disclosures Jennifer Han, MD, MSCE, GlaxoSmithKline (Employee, Shareholder) Ebbing Lautenbach, MD, MPH, MSCE, Merck (Other Financial or Material Support, Member of Data and Safety Monitoring Board (DSMB)) Pranita Tamma, MD, MHS, Nothing to disclose Emily Blumberg, MD, Amplyx (Other Financial or Material Support, Member of Data and Safety Monitoring Board (DSMB))Hologic (Research Grant or Support)Merck (Grant/Research Support, Other Financial or Material Support, Member of Scientific Advisory Committee)Takeda (Research Grant or Support, Other Financial or Material Support, Member of Scientific Advisory Committee) Judith A. Anesi, MD, MSCE, Nothing to disclose

A Comparison Between Cefepime and Piperacillin-Tazobactam in the Management of Septic Shock.

IntroductionSeptic shock is defined as a dysregulated host response to infection characterized by hemodynamic instability. Concern for the increased risk of acute kidney injury (AKI) with piperacillin-tazobactam in combination with vancomycin may prompt more use of alternative broad-spectrum antipseudomonal beta-lactam antibiotics, such as cefepime. This study assessed whether cefepime was associated with improved outcomes compared to piperacillin-tazobactam in patients with septic shock.MethodsThis retrospective cohort study included veterans treated for septic shock between September 1, 2008, and August 31, 2018. This study compared cefepime and piperacillin-tazobactam as initial antibiotic management for septic shock. Outcomes included AKI, Clostridioides difficile infection (CDI), hospital length of stay, intensive care unit mortality, and mortality within 30 days of hospitalization.ResultsIn total, 240 patients were included in this study (120 in each cohort). The proportion of AKI was 60.0% in the piperacillin-tazobactam cohort compared to 58.3% in the cefepime cohort (p = 0.90). Mortality was significantly higher in the cefepime cohort. There were no significant differences in CDI or hospital length of stay.ConclusionThe results of this study do not suggest that the use of the antipseudomonal beta-lactam antibiotic used in the initial management of septic shock is associated with differences in the AKI or CDI. The higher mortality observed with cefepime may warrant further investigation.

Antibiotics in Necrotizing Soft Tissue Infections.

Necrotizing soft tissue infections (NSTIs) are rare life-threatening bacterial infections characterized by an extensive necrosis of skin and subcutaneous tissues. Initial urgent management of NSTIs relies on broad-spectrum antibiotic therapy, rapid surgical debridement of all infected tissues and, when present, treatment of associated organ failures in the intensive care unit. Antibiotic therapy for NSTI patients faces several challenges and should (1) carry broad-spectrum activity against gram-positive and gram-negative pathogens because of frequent polymicrobial infections, considering extended coverage for multidrug resistance in selected cases. In practice, a broad-spectrum beta-lactam antibiotic (e.g., piperacillin-tazobactam) is the mainstay of empirical therapy; (2) decrease toxin production, typically using a clindamycin combination, mainly in proven or suspected group A streptococcus infections; and (3) achieve the best possible tissue diffusion with regards to impaired regional perfusion, tissue necrosis, and pharmacokinetic and pharmacodynamic alterations. The best duration of antibiotic treatment has not been well established and is generally comprised between 7 and 15 days. This article reviews the currently available knowledge regarding antibiotic use in NSTIs.

English

Escherichia coli and Klebsiella pneumoniae are pathogens frequently involved in urinary tract infections with high epidemic potential. The increase and spread resistance of these microbes to broad spectrum beta-lactam antibiotics are usually reported and is a real public health concern in Cote d’Ivoire but information on genetic variants and intragenic mutations encoding these resistances are scarce. The aim of this study is to characterize genetic variants and describe the intragenic mutations underlying resistance to broad-spectrum beta-lactam antibiotics in uropathogen E. coli and K. pneumoniae in HKB and CHR hospitals with different epidemiological facies in Cote d’Ivoire. 39 strains comprising 30 of E. coli and 9 strains of K. pneumoniae were isolated from which DNA was extracted, amplified and sequenced. ESBLs genes were detected by polymerase chain reaction in 58.8 % of strain analysis. No significant difference was observed between ESBL from HKB and CHR hospitals although HKB and CHR sites present 50 and 56.8% of ESBL respectively. Nucleotide sequences subjected to BLASTn for sequences similarity and homology revealed diversity of resistance genes with dominance of the gene encoding the extended-spectrum β-lactamase CTX-M-15 and the emergence of a new blaTEM-9 gene in Cote d'Ivoire. The significant co-expression of ESBLs might impact 3rd generation cephalosporin multi-resistance among pathogenic bacteria infecting patient population. Routine antibiogram practice could guide the choice of optimal antibiotic therapy for successful treatment and delay the occurrence of multidrug resistance in enterobacterial infections. Key words: Urinary tract infection, extended-spectrum β-lactamase, gene variants, mutations, antibiotic resistance, Cote d’Ivoire.

BlaNDM gene identified from clinical samples of companion animals: First description in Brazil

Background: Emergence of acquired carbapenemases and their worldwide dissemination are a major global threat to antibiotic era and represent a major clinical challenge in both human and veterinary contexts. Carbapenems are broad-spectrum beta-lactam antibiotics employed for treatment of serious infections, usually considered as the last-line available therapy against multidrug-resistant (MDR) Gram-negative bacterial infections like those caused by extended spectrum beta-lactamase (ESBL) pathogens. The New Delhi metallo-beta-lactamase (NDM) was named after being discovered in India, in 2009, and has been isolated in several parts of the world. Until now, the occurrence of NDM appeared to be restricted mainly to humans, however the prevalence and characteristics of MDR genes in Enterobacteriaceae originating from companion animals are still not well known. Thus, this study aimed to investigate the occurrence of carbapenemase encoding genes in bacteria resistant to carbapenems, isolated from clinical samples of companion animals. Methods and materials: There were considered bacterial isolates from dogs (97 strains) and cats (24 isolates) showing phenotypic resistance to carbapenems, identified during routine microbiological investigation between July 2018 and April 2019 in Joinville, Southern Brazil. Phenotypic resistance to carbapenems and the susceptibility profile to other common antimicrobials were determined by the disc-diffusion agar method. In addition, Modified Carbapenem Inactivation Method (mCIM) was used for phenotypic confirmation of carbapenemases in Enterobacteriaceae. The presence of blaNDM gene was confirmed by Real-time Polymerase Chain Reaction employing TaqMan probes. Results: In this study, there were identified two MDR isolates (Klebsiella pneumoniae and Enterobacter cloacae) carrying the blaNDM gene derived from dogs urine. Conclusion: To our knowledge, this is the first report of NDM identified in clinical isolates derived from companion animals in Brazil. Of note, the blaNDM gene may be located in readily transferable plasmids, increasing the variety of transmission vectors of resistance to carbapenems, also considering that the species carrying the gene identified in this study are widely distributed and shared among the environment, animals and humans.

Risk factors for development of vancomycin-resistant enterococcal bacteremia among VRE colonizers : Aretrospective case control study.

We aimed to determine the proportion of vancomycin-resistant enterococci (VRE) colonized patients among all inpatients who later developed VRE bacteremia during hospital stay and to identify the risk factors for VRE bacteremia at atertiary hospital. Patients with positive rectal screening or any clinically significant positive culture results for VRE were included in 1‑year follow-up. Colonization with VRE was defined as apositive culture (rectal, stool, urinary) for VRE without infection and VRE bacteremia was defined as positive blood culture if the signs and symptoms were compatible with infection. To determine the risk factors for VRE bacteremia among VRE colonized patients, aretrospective case control study was performed. The two groups were compared in terms of variables previously defined as risk factors in the literature. Of 947 positive samples, 17VRE bacteremia were included in the analysis. Cephalosporin use for more than 3days within 3months was asignificant risk factor for bacteremia (p = 0.008). Prior use of carbapenems was found to be statistically significant for bacteremia (p = 0.007). In multivariate analyses the use of carbapenems and cephalosporins was an independent risk factor for developing bacteremia among VRE colonizers (odds ratio, OR, 6.67; 95% confidence interval, CI, 1.30-34; p = 0.022 and OR 4.32, 95% CI 1.23-15; p = 0.022, respectively). AVRE colonization in patients receiving broad-spectrum beta-lactam antibiotics including carbapenems and cephalosporins may result in bacteremia. It is possible to keep mortality at very low levels in VRE bacteremia with effective infection control measures, rapid infectious diseases consultation and rational antimicrobial treatment based on current epidemiological data.

Genomic profiling of Escherichia coli isolates from bacteraemia patients: a 3-year cohort study of isolates collected at a Sydney teaching hospital.

This study sought to assess the genetic variability of Escherichia coli isolated from bloodstream infections (BSIs) presenting at Concord Hospital, Sydney during 2013–2016. Whole-genome sequencing was used to characterize 81 E. coli isolates sourced from community-onset (CO) and hospital-onset (HO) BSIs. The cohort comprised 64 CO and 17 HO isolates, including 35 multidrug-resistant (MDR) isolates exhibiting phenotypic resistance to three or more antibiotic classes. Phylogenetic analysis identified two major ancestral clades. One was genetically diverse with 25 isolates distributed in 16 different sequence types (STs) representing phylogroups A, B1, B2, C and F, while the other comprised phylogroup B2 isolates in subclades representing the ST131, ST73 and ST95 lineages. Forty-seven isolates contained a class 1 integron, of which 14 carried bla CTX -M-gene. Isolates with a class 1 integron carried more antibiotic resistance genes than isolates without an integron and, in most instances, resistance genes were localized within complex resistance loci (CRL). Resistance to fluoroquinolones could be attributed to point mutations in chromosomal parC and gyrB genes and, in addition, two isolates carried a plasmid-associated qnrB4 gene. Co-resistance to fluoroquinolone and broad-spectrum beta-lactam antibiotics was associated with ST131 (HO and CO), ST38 (HO), ST393 (CO), ST2003 (CO) and ST8196 (CO and HO), a novel ST identified in this study. Notably, 10/81 (12.3 %) isolates with ST95 (5 isolates), ST131 (2 isolates), ST88 (2 isolates) and a ST540 likely carry IncFII–IncFIB plasmid replicons with a full spectrum of virulence genes consistent with the carriage of ColV-like plasmids. Our data indicate that IncF plasmids play an important role in shaping virulence and resistance gene carriage in BSI E. coli in Australia.

Novel insights into the chemistry of an old medicine: A general degradative pathway for penicillins from a piperacillin/tazobactam stability study

Piperacillin is a broad spectrum beta-lactam antibiotic used in combination with tazobactam for hospital-related bacterial infections. The reconstituted solutions must respect the sub-visible and visible particles specifications. It was claimed that the reformulation containing EDTA/sodium citrate was able to control the formation of an insoluble impurity responsible for the formation of particulate matter observed using Ringer Lactate as diluent. The nature of the impurities formed during the degradative process of piperacillin/tazobactam combination has been herein investigated, by exploring the effect of added excipients and pH variations. The exact structure of the isolated dimeric impurity, the penicilloic acid-piperacillin dimer, was determined through complete characterization, allowing to propose a novel degradative general pathway for beta-lactam antibiotics. The presence of EDTA resulted unnecessary to contain the formation of the insoluble impurity, since the use of sodium citrate alone allowed to avoid this drawback. Finally, the proposed mechanism was successfully applied to the design of a novel, easy and high purity procedure for the synthesis of the acetylated penicilloic acid, known related substance of piperacillin.

Impact of Levofloxacin for the Prophylaxis of Bloodstream Infection on the Gut Microbiome in Patients With Hematologic Malignancy

BackgroundWe evaluated the differential impact of levofloxacin administered for the prophylaxis of bloodstream infections compared with broad-spectrum beta-lactam (BSBL) antibiotics used for the treatment of neutropenic fever on the gut microbiome in patients with hematologic malignancy.MethodsStool specimens were collected from patients admitted for chemotherapy or stem cell transplant in the setting of the evaluation of diarrhea from February 2017 until November 2017. Microbiome characteristics were compared among those exposed to levofloxacin prophylaxis vs those who received BSBL antibiotics.ResultsSixty patients were included, most with acute myeloid leukemia (42%) or multiple myeloma (37%). The gut microbiome of patients with BSBL exposure had significantly reduced Shannon’s alpha diversity compared with those without (median [interquartile range {IQR}], 3.28 [1.73 to 3.71] vs 3.73 [3.14 to 4.31]; P = .01). However, those with levofloxacin exposure had increased alpha diversity compared with those without (median [IQR], 3.83 [3.32 to 4.36] vs 3.32 [2.35 to 4.02]; P = .03). Levofloxacin exposure was also associated with a trend toward lower risk of dominance of non-Bacteroidetes genera compared with those without levofloxacin exposure (3 [14%] vs 15 [38%]; P = .051).ConclusionsThe impact of antibiotics on the gut microbiome varies by class, and levofloxacin may disrupt the gut microbiome less than BSBLs in this patient population.

Faecal colonization of E. coli and Klebsiella spp. producing extended-spectrum beta-lactamases and plasmid-mediated AmpC in Mozambican university students

BackgroundIn recent years, the world has seen a surge in Enterobacteriaceae resistant to broad-spectrum beta-lactam antibiotics due to the production of extended-spectrum beta-lactamases (ESBLs) or plasmid-mediated AmpC (pAmpC) enzymes. Data on the epidemiology of cephalosporin-resistant Enterobacteriaceae in Sub-Saharan Africa are still limited.MethodsTwo hundred seventy-five non-repetitive stool samples were collected from Mozambican university students of both sexes. Samples were cultured on MacConkey agar with and without ceftriaxone (1 mg/L) for selection of third-generation cephalosporin-resistant isolates, which were subjected to antimicrobial susceptibility testing by disc diffusion, characterization of resistance genes by PCR and ERIC-PCR analysis for strain clonality.ResultsAmong the 275 students, 55 (20%) carried a total of 56 E. coli (n = 35) and Klebsiella spp. (n = 21) isolates resistant to ceftriaxone and phenotypically positive for ESBL- and/or pAmpC-production. Forty-three percent of the isolates (24/56) contained only ESBL genes, 11% (6/56) only pAmpC genes, and 36% (20/56) both ESBL and pAmpC genes. The remaining six isolates were negative for the CTX-M/pAmpC genes included in the test panel. E. coli and Klebsiella spp. combined demonstrated 70% resistance to tetracycline and co-trimoxazole, 63% to ceftazidime and 34% to ciprofloxacin. In total, 89% of ESBL/pAmpC-positive isolates were defined as multi-resistant by being resistant to three or more antibiotic classes. ERIC-PCR fingerprinting demonstrated low similarity among isolates. None of the participants reported recent hospitalization and just 12.5% had taken antibiotics 3 months prior to the study.ConclusionThis study demonstrated 20% colonization with multi-resistant E. coli and Klebsiella spp. among Mozambican students with a diversity of ESBL and pAmpC genes. Colonization was not related to prior hospitalization or antimicrobial consumption.

Population pharmacokinetics of continuous infusion of piperacillin in critically ill patients

Dosing recommendations for continuous infusion of piperacillin, a broad-spectrum beta-lactam antibiotic, are mainly guided by outputs from population pharmacokinetic models constructed with intermittent infusion data. However, the probability of target attainment in patients receiving piperacillin by continuous infusion may be overestimated when drug clearance estimates from population pharmacokinetic models based on intermittent infusion data are used, especially when higher doses (e.g. 16 g/24 h or more) are simulated. Therefore, the purpose of this study was to describe the population pharmacokinetics of piperacillin when infused continuously in critically ill patients. For this analysis, 270 plasma samples from 110 critically ill patients receiving piperacillin were available for population pharmacokinetic model building. A one-compartment model with linear clearance best described the concentration–time data. The mean ± standard deviation parameter estimates were 8.38 ± 9.91 L/h for drug clearance and 25.54 ± 3.65 L for volume of distribution. Creatinine clearance improved the model fit and was supported for inclusion as a covariate. In critically ill patients with renal clearance higher than 90 mL/min/1.73 m2, a high-dose continuous infusion of 24 g/24 h is insufficient to achieve adequate exposure (pharmacokinetic/pharmacodynamic target of 100% fT>4 x MIC) against susceptible Pseudomonas aerginosa isolates (MIC ≤16 mg/L). These findings suggest that merely increasing the dose of piperacillin, even with continuous infusion, may not always result in adequate piperacillin exposure. This should be confirmed by evaluating piperacillin target attainment rates in critically ill patients exhibiting high renal clearance.

Ultrahigh antibacterial efficacy of meropenem-loaded chitosan nanoparticles in a septic animal model

Antimicrobial resistance is one of the most significant health challenges worldwide. Meropenem is a broad spectrum beta-lactam antibiotic that possesses high activity against Gram-positive and Gram-negative bacteria. However, it has a short plasma half-life, and thus requiring frequent administration of high doses. For the first time, meropenem-loaded chitosan nanoparticles were prepared and evaluated as a potential tool to overcome antimicrobial resistance and to improve pharmacokinetics of the drug. Spherical nanosized particles were prepared and demonstrated ultrahigh encapsulation efficiency of meropenem (i.e. 76.3%). The nanoparticles could be stored in a freeze-dried powdered form while maintaining their physicochemical characteristics. In vitro, higher antibacterial activities of the drug-loaded nanoparticles were observed against methicillin-sensitive and methicillin-resistant Staphylococcus aureus, Escherichia coli and Klebsiella pneumoniae, as compared to the free drug. The nanoparticles were then tested in a septic rat model of Klebsiella pneumoniae and showed exceptional improvement of survival and bacterial clearance, as compared to the animals treated with the free drug. Hence, meropenem-loaded chitosan nanoparticles might have great potential for overcoming antimicrobial resistance.

Restrictive antibiotic stewardship associated with reduced hospital mortality in gram-negative infection.

: Antimicrobial stewardship has an important role in the control of Clostridium difficile infection (CDI) and antibiotic resistance. An important component of UK stewardship interventions is the restriction of broad-spectrum beta-lactam antibiotics and promotion of agents associated with a lower risk of CDI such as gentamicin. While the introduction of restrictive antibiotic guidance has been associated with improvements in CDI and antimicrobial resistance, evidence of the effect on outcome following severe infection is lacking. : In 2008, Glasgow hospitals introduced a restrictive antibiotic guideline. A retrospective before/after study assessed outcome following Gram-negative bacteraemia in the 2-year period around implementation. : Introduction of restrictive antibiotic guidelines was associated with a reduction in utilization of ceftriaxone and co-amoxiclav and an increase in amoxicillin and gentamicin. Approximately 1593 episodes of bacteremia were included in the study. The mortality over 1-year following Gram-negative bacteraemia was lower in the period following guideline implementation (RR 0.852, P = 0.045). There was no evidence of a difference in secondary outcomes including ITU admission, length of stay, readmission, recurrence of bacteraemia and need for renal replacement therapy. There was a fall in CDI (RR 0.571, P = 0.014) and a reduction in bacterial resistance to ceftriaxone and co-amoxiclav but no evidence of an increase in gentamicin resistance after guideline implementation. : Restrictive antibiotic guidelines were associated with a reduction in CDI and bacterial resistance but no evidence of adverse outcomes following Gram-negative bacteraemia. There was a small reduction in one year mortality.