Antibiotics, Volume 5, Issue 1 (March 2016) – 13 articles

The incidence of Clostridium difficile infection (CDI) in the UK rose dramatically during the early years of this century, in part associated with the emergence of the hyper-virulent ribotype 027 strain. The University Hospitals of Leicester (UHL), a 2000-bed acute UK NHS Trust, implemented a number of interventions, which led to an 80% reduction in new cases over a twelve month period. Changes were introduced as a result of collaboration between the Infection Prevention team, the departments of Microbiology and Infectious Diseases, and with the support of the Trust Executive. These strategies are described in detail and included; implementation of antimicrobial stewardship, specific hygiene and cleaning measures, the introduction of a care pathway form for all infected patients, the opening of an isolation ward for patients with CDI, strengthened organisation and clinical management, and rigorous attention to education within the Trust. The implementations described are of continued relevance in the face of new infection challenges, such as the increasing incidence of multi-drug resistant organisms. Full article

Peptidoglycan (PG) is an essential macromolecular sacculus surrounding most bacteria. It is assembled by the glycosyltransferase (GT) and transpeptidase (TP) activities of multimodular penicillin-binding proteins (PBPs) within multiprotein complex machineries. Both activities are essential for the synthesis of a functional stress-bearing PG shell. Although good progress has been made in terms of the functional and structural understanding of GT, finding a clinically useful antibiotic against them has been challenging until now. In contrast, the TP/PBP module has been successfully targeted by β-lactam derivatives, but the extensive use of these antibiotics has selected resistant bacterial strains that employ a wide variety of mechanisms to escape the lethal action of these antibiotics. In addition to traditional β-lactams, other classes of molecules (non-β-lactams) that inhibit PBPs are now emerging, opening new perspectives for tackling the resistance problem while taking advantage of these valuable targets, for which a wealth of structural and functional knowledge has been accumulated. The overall evidence shows that PBPs are part of multiprotein machineries whose activities are modulated by cofactors. Perturbation of these systems could lead to lethal effects. Developing screening strategies to take advantage of these mechanisms could lead to new inhibitors of PG assembly. In this paper, we present a general background on the GTs and TPs/PBPs, a survey of recent issues of bacterial resistance and a review of recent works describing new inhibitors of these enzymes. Full article

Antimicrobial stewardship programs (ASPs) focus on improving the utilization of broad spectrum antibiotics to decrease the incidence of multidrug-resistant Gram positive and Gram negative pathogens. Hospital admission for both medical and surgical intra-abdominal infections (IAIs) commonly results in the empiric use of broad spectrum antibiotics such as fluoroquinolones, beta-lactam beta-lactamase inhibitors, and carbapenems that can select for resistant organisms. This review will discuss the management of uncomplicated and complicated IAIs as well as highlight stewardship initiatives focusing on the proper use of broad spectrum antibiotics. Full article

WaaG is a glycosyltransferase that is involved in the biosynthesis of lipopolysaccharide in Gram-negative bacteria. Inhibitors of WaaG are highly sought after as they could be used to inhibit the biosynthesis of the core region of lipopolysaccharide, which would improve the uptake of antibiotics. Herein, we establish an activity assay for WaaG using ¹⁴C-labeled UDP-glucose and LPS purified from a ∆waaG strain of Escherichia coli. We noted that addition of the lipids phosphatidylglycerol (PG) and cardiolipin (CL), as well as the detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS) increased activity. We then use the assay to determine if three molecular scaffolds, which bind to WaaG, could inhibit its activity in vitro. We show that 4-(2-amino-1,3-thiazol-4-yl)phenol inhibits WaaG (IC₅₀ 1.0 mM), but that the other scaffolds do not. This study represents an important step towards an inhibitor of WaaG by fragment-based lead discovery. Full article

Antimicrobial resistance is a growing public health concern. Antimicrobial stewardship and multi-disciplinary intervention can prevent inappropriate antimicrobial use and improve patient care. Special populations, especially older adults and patients with mental health disorders, can be particularly in need of such intervention. The purpose of this project was to assess the impact of pharmacist intervention on appropriateness of antimicrobial prescribing on a geriatric psychiatric unit (GPU). Patients ≥18 years old prescribed oral antibiotics during GPU admission were included. Antimicrobial appropriateness was assessed pre- and post-pharmacist intervention. During the six-month pre- and post-intervention phase, 63 and 70 patients prescribed antibiotics were identified, respectively. Subjects in the post-intervention group had significantly less inappropriate doses for indication compared to the pre-intervention group (10.6% vs. 23.9%, p = 0.02), and significantly less antibiotics prescribed for an inappropriate duration (15.8% vs. 32.4%, p < 0.01). There were no significant differences for use of appropriate drug for indication or appropriate dose for renal function between groups. Significantly more patients in the post intervention group had medications prescribed with appropriate dose, duration, and indication (51% vs. 66%, p = 0.04). Pharmacist intervention was associated with decreased rates of inappropriate antimicrobial prescribing on a geriatric psychiatric unit. Full article

Allergies to β-lactam antibiotics are commonly documented in hospitalized patients; however, true allergy is uncommon. Cross-reactivity rates for advanced generation cephalosporins and carbapenems are low; particularly for patients without a history of symptoms consistent with type 1 hypersensitivity. We observed that providers preferentially prescribed antipseudomonal carbapenems (APC) over advanced generation cephalosporins for patients with β-lactam allergy history, including those with low risk for antimicrobial-resistant infections. Information was inserted into the computerized decision support system (CDSS) to aid clinicians in assessing β-lactam cross-reactivity risk and selecting appropriate therapy. A retrospective evaluation was conducted in a small hospital to assess the impact of the CDSS changes in APC prescribing. Inpatients (n = 68) who received at least one APC dose during hospitalization over a 13 month pre-intervention period were compared to inpatients who received an APC during the 15 month post-intervention period (n = 59) for documented APC indications and β-lactam allergy history. APC initiations were measured and corrected per 1000 patient-days; interrupted time-series analysis was performed to assess changes in use before and after implementation. Aggregate monthly APC initiations decreased from 7.01 to 6.14 per 1000 patient-days after the implementation (p = 0.03). Post-intervention APC initiations for patients with low-risk β-lactam histories decreased from 92% to 83% (p = 0.17). No adverse events were observed in patients with low-risk β-lactam histories. The intervention was associated with a reduction in APC initiations. Full article

Antimicrobial stewardship programs (ASPs) are challenged with ensuring appropriate antimicrobial use while minimizing expenditures. ASPs have consistently demonstrated improved patient outcomes and significant cost reductions but are continually required to justify the costs of their existence and interventions due to the silo mentality often adopted by hospital administrators. As new technologies and antimicrobials emerge, ASPs are in a constant tug-of-war between providing optimal clinical outcomes and ensuring cost containment. Additionally, robust data on cost-effectiveness of new rapid diagnostic technologies and antimicrobials with subsequent ASP interventions to provide justification are lacking. As the implementation of an ASP will soon be mandatory for acute care hospitals in the United States, ASPs must find ways to justify novel interventions to align themselves with healthcare administrators. This review provides a framework for the justification of implementing a rapid diagnostic test or adding a new antimicrobial to formulary with ASP intervention, reviews approaches to demonstrating cost-effectiveness, and proposes methods for which ASPs may reduce healthcare expenditures via alternative tactics. Full article

The growing problem of antimicrobial resistance (AMR) has led to calls for antimicrobial stewardship programs (ASP) to control antibiotic use in healthcare settings. Key strategies include prospective audit with feedback and intervention, and formulary restriction and preauthorization. Education, guidelines, clinical pathways, de-escalation, and intravenous to oral conversion are also part of some programs. Impact and quality of ASP can be assessed using process or outcome measures. Outcome measures are categorized as microbiological, patient or financial outcomes. The objective of this review was to provide an overview of quality measures for assessing ASP and the reported impact of ASP in peer-reviewed studies, focusing particularly on patient outcomes. A literature search of papers published in English between 1990 and June 2015 was conducted in five databases using a combination of search terms. Primary studies of any design were included. A total of 63 studies were included in this review. Four studies defined quality metrics for evaluating ASP. Twenty-one studies assessed the impact of ASP on antimicrobial utilization and cost, 25 studies evaluated impact on resistance patterns and/or rate of Clostridium difficile infection (CDI). Thirteen studies assessed impact on patient outcomes including mortality, length of stay (LOS) and readmission rates. Six of these 13 studies reported non-significant difference in mortality between pre- and post-ASP intervention, and five reported reductions in mortality rate. On LOS, six studies reported shorter LOS post intervention; a significant reduction was reported in one of these studies. Of note, this latter study reported significantly (p < 0.001) higher unplanned readmissions related to infections post-ASP. Patient outcomes need to be a key component of ASP evaluation. The choice of metrics is influenced by data and resource availability. Controlling for confounders must be considered in the design of evaluation studies to adequately capture the impact of ASP and it is important for unintended consequences to be considered. This review provides a starting point toward compiling standard outcome metrics for assessing ASP. Full article

The presence of antimicrobial resistance and virulence factors of 174 Escherichia coli strains isolated from healthy Portuguese Gallus gallus was evaluated. Resistance profiles were determined against 33 antimicrobials by microbroth dilution. Resistance was prevalent for tetracycline (70%) and ampicillin (63%). Extended-spectrum beta-lactamase (ESBL) phenotype was observed in 18% of the isolates. Multidrug resistance was found in 56% of isolates. A subset of 74 isolates were screened by DNA microarrays for the carriage of 88 antibiotic resistance genes and 62 virulence genes. Overall, 37 different resistance genes were detected. The most common were tet(A) (72%), bla_TEM (68%), and sul1 (47%), while 21% isolates harbored an ESBL gene (bla_CTX-M group 1, group 2, or group 9). Of these, 96% carried the increased serum survival (iss) virulence gene, while 89% presented the enterobactin siderophore receptor protein (iroN), 70% the temperature-sensitive hemagglutinin (tsh), and 68% the long polar fimbriae (lpfA) virulence genes associated with extraintestinal pathogenic E. coli. In conclusion, prevalence of antibiotic resistant E. coli from the microbiota of Portuguese chickens was high, including to extended spectrum cephalosporins. The majority of isolates seems to have the potential to trigger extraintestinal human infection due to the presence of some virulence genes. However, the absence of genes specific for enteropathogenic E. coli reduces the risk for human intestinal infection. Full article

Most bacteria attach to surfaces where they form a biofilm, cells embedded in a complex matrix of polymers. Cells in biofilms are much better protected against noxious agents than free-living cells. As a consequence it is very difficult to control pathogens with antibiotics in biofilm infections and novel targets are urgently needed. One approach aims at the communication between cells to form and to maintain a biofilm, a process called quorum-sensing. Water soluble small-sized molecules mediate this process and a number of antagonists of these compounds have been found. In this review natural compounds and synthetic drugs which do not interfere with the classical quorum-sensing compounds are discussed. For some of these compounds the targets are still not known, but others interfere with the formation of exopolysaccharides, virulence factors, or cell wall synthesis or they start an internal program of biofilm dispersal. Some of their targets are more conserved among pathogens than the receptors for quorum sensing autoinducers mediating quorum-sensing, enabling a broader application of the drug. The broad spectrum of mechanisms, the diversity of bioactive compounds, their activity against several targets, and the conservation of some targets among bacterial pathogens are promising aspects for several clinical applications of this type of biofilm-controlling compound in the future. Full article

This study evaluates drug cost outcomes related to automatic therapeutic substitution of branded tobramycin solution for inhalation (TOBI^®) with inhaled generic preservative-free intravenous tobramycin (PFIT). A retrospective single-center evaluation of inhaled tobramycin use from 2008 through 2012 was performed. Number of doses dispensed and acquisition costs were obtained. Hourly wage data was acquired, pharmacy production costs were estimated and total cost-savings calculated. Days of therapy (DOTs) were determined for each year. Quality assurance and safety data was collected. In 2008, TOBI^® drug costs and doses dispensed were $118,665 and 1769, respectively. Following implementation of the interchange in May 2009, TOBI^® utilization ceased. PFIT costs in 2010 through 2012 averaged $34,775 annually and TOBI^® cost-avoidance exceeded $94,000 annually when accounting for pharmacy production costs, which were determined to be at most $5.28 per dose. The maximum estimated pharmacy production cost ranged from $8812 to $11,299 annually. PFIT doses dispensed exceeded 1650 each year and annual DOTs ranged from 815 to 1069. The 40-month savings were calculated to be $374,706. Quality assurance and safety data identified one patient who refused PFIT due to odor complaints and one patient who was inappropriately administered a dose orally. Therapeutic substitution of TOBI^® with PFIT can produce immediate and sustained savings with an acceptable safety profile. Full article

The use of medicated feed is a common practice in animal food production to improve animal health. Tetracyclines and β-Lactams are the groups that are most frequently added to this type of feed. The measurement of the concentration of the analytes in these types of samples is sometimes due to the matrix characteristic, and manufacturers are demanding fast, precise and reproducible methods. A rapid confirmatory method based on a simple extraction protocol using acidified methanol and followed by high performance liquid chromatography coupled to a tandem mass spectrometer for the quantification of four tetracyclines in feed is presented. Validation was performed following the guidelines of Decision 2002/657/EC. Results indicated that the four tetracyclines can be identified and quantified in a concentration range between 50 and 500 mg/kg with recoveries between 84% and 109% and RSD for precision under reproducible conditions between 12% and 16%. Satisfactory results were also obtained with interlaboratory studies and by comparing the method with an HPLC-Fluorescent method. Full article