Impact of sodium-glucose cotransporter-2 inhibitors on heart failure and mortality in patients with cancer.

OBJECTIVES: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) reduce heart failure (HF) in at-risk patients and may possess antitumour effects. We examined the effect of SGLT2i on HF and mortality among patients with cancer and diabetes. METHODS: This was a retrospective propensity score-matched cohort study involving adult patients with type 2 diabetes mellitus diagnosed with cancer between January 2010 and December 2021. The primary outcomes were hospitalisation for incident HF and all-cause mortality. The secondary outcomes were serious adverse events associated with SGLT2i. RESULTS: From a total of 8640 patients, 878 SGLT2i recipients were matched to non-recipients. During a median follow-up of 18.8 months, SGLT2i recipients had a threefold lower rate of hospitalisation for incident HF compared with non-SGLT2i recipients (2.92 vs 8.95 per 1000 patient-years, p=0.018). In Cox regression and competing regression models, SGLT2i were associated with a 72% reduction in the risk of hospitalisation for HF (HR 0.28 (95% CI: 0.11 to 0.77), p=0.013; subdistribution HR 0.32 (95% CI: 0.12 to 0.84), p=0.021). The use of SGLT2i was also associated with a higher overall survival (85.3% vs 63.0% at 2 years, p<0.001). The risk of serious adverse events such as hypoglycaemia and sepsis was similar between the two groups. CONCLUSIONS: The use of SGLT2i was associated with a lower rate of incident HF and prolonged overall survival in patients with cancer with diabetes mellitus.

Manifestations and mechanisms of myocardial lipotoxicity in obesity.

Environmental and socioeconomic changes over the past thirty years have contributed to a dramatic rise in the worldwide prevalence of obesity. Heart disease is amongst the most serious health risks of obesity, with increases in both atherosclerotic coronary heart disease and heart failure among obese individuals. In this review, we focus on primary myocardial alterations in obesity that include hypertrophic remodelling and diastolic dysfunction. Obesity-associated perturbations in myocardial and systemic lipid metabolism are important contributors to cardiovascular complications of obesity. Accumulation of excess lipid in nonadipose cells of the cardiovascular system can cause cell dysfunction and cell death, a process known as lipotoxicity. Lipotoxicity has been modelled in mice using high-fat diet feeding, inbred lines with mutations in leptin receptor signalling, and in genetically engineered mice with enhanced myocardial fatty acid uptake, altered lipid droplet homoeostasis or decreased cardiac fatty acid oxidation. These studies, along with findings in cell culture model systems, indicate that the molecular pathophysiology of lipid overload involves endoplasmic reticulum stress, alterations in autophagy, de novo ceramide synthesis, oxidative stress, inflammation and changes in gene expression. We highlight recent advances that extend our understanding of the impact of obesity and altered lipid metabolism on cardiac function.

Multicenter evaluation of the Cepheid Xpert methicillin-resistant Staphylococcus aureus (MRSA) test as a rapid screening method for detection of MRSA in nares.

The first U.S. multicenter clinical trial to assess the performance of the Cepheid Xpert MRSA assay (Xpert MRSA) was conducted. The assay is a qualitative test designed for the rapid detection of methicillin-resistant Staphylococcus aureus (MRSA) directly from nares swabs. This novel test combines integrated nucleic acid extraction and automated real-time PCR for the detection of a MRSA-specific signature sequence. A total of 1,077 nares specimens were collected from seven geographically distinct health care sites across the United States with prevalence rates ranging from 5.2% to 44%. Nares specimens were tested by (i) the Xpert MRSA assay, (ii) direct culture on CHROMagar MRSA medium (direct CM culture), and (iii) broth-enriched culture (Trypticase soy broth with 6.5% sodium chloride) followed by plating onto CHROMagar MRSA medium (broth-enriched CM culture). When direct CM culture was designated the reference method, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the Xpert MRSA assay were 94.3%, 93.2%, 73.0%, and 98.8%, respectively. When broth-enriched CM culture was used as the reference method, the clinical sensitivity, specificity, PPV, and NPV of the Xpert MRSA assay were 86.3%, 94.9%, 80.5%, and 96.6%, respectively. The BD GeneOhm MRSA (BDGO) assay was performed as a comparative molecular method. No statistical performance differences were observed between the Xpert MRSA and BDGO assays when they were compared to culture methods. From this large-scale, multicenter clinical comparison, we conclude that the Xpert MRSA assay is a simple, rapid, and accurate method for performing active surveillance for MRSA in a variety of health care populations.

Currently available antimicrobial agents and their potential for use as monotherapy.

Infectious diseases remain a serious and now re-emerging threat to human life, contributing to over ten million deaths per year. Treatment of major infectious diseases with antibacterial agents creates an ongoing and escalating public health issue that currently leads to more problems than solutions. By processes of adaptation and survival, bacteria consistently develop mechanisms to overcome the effects of the newest and most potent antibacterial compounds. Simultaneously, progressively fewer antibacterial agents are being developed by pharmaceutical and biotechnology companies. Although this dilemma is an inherent trade-off and has no imminent resolution, the most prudent paradigm to pursue is the judicious use of antibacterial agents in the most limited way possible to attain the desired treatment results. One straightforward approach to antimicrobial stewardship is to use a single agent as opposed to combination therapy, so as to subject bacteria to lower total antibiotic exposure whenever feasible. This article reviews current trends in antibacterial drug development and describes a context for adherence to monotherapy with newer agents.

Antibiotic policy and prescribing strategies for therapy of extended-spectrum beta-lactamase-producing Enterobacteriaceae: the role of piperacillin-tazobactam.

Therapy of infections caused by extended-spectrum beta-lactamase (ESBL)-producing bacteria with an antimicrobial to which they are resistant results in treatment failure, higher cost and increased mortality. The CLSI recommends reporting ESBL-producing strains of Escherichia coli, Klebsiella spp. and Proteus spp. as resistant to all penicillin, true cephalosporin and monobactam antimicrobials, but as susceptible to beta-lactam-beta-lactamase inhibitor combinations, including piperacillin-tazobactam, when they test as such. Current literature supports the action of piperacillin-tazobactam against susceptible strains of ESBL-producing bacteria based on the structure-activity relationship between inhibitors and the ESBLs, as well as on recent clinical outcome studies.

Squeezing the antibiotic balloon: the impact of antimicrobial classes on emerging resistance.

The ongoing problem of emerging antimicrobial resistance has been likened to a balloon where settling one specific issue results in a 'bulge' of even worse problems. However, much has been learned about how to best use our critical antibacterial agents in ways to avoid or even repair some of the resistance damage that has been done. A compilation of current literature strongly suggests that to slow the development of resistance to antimicrobial agents it is optimal to use drugs with more than one mechanism of action or target, to prescribe those with demonstrated ability to minimise or reverse resistance problems, and to avoid underdosing of potent antibiotics. The most recent information also indicates that it is best to limit empirical use of beta-lactam plus fluoroquinolone combination therapy, since these two classes activate some common resistance responses, and using them together can facilitate multidrug resistance in important pathogens, particularly Pseudomonas aeruginosa and Acinetobacter species. This review discusses the role of each major antimicrobial class on resistance development and presents specific strategies for combating the growing problem of multidrug-resistant bacteria. We now have the knowledge to better manage our antimicrobial agent prescribing practices, but finding the will and resources to apply our understanding remains a formidable challenge.

Detection of vancomycin-resistant enterococci before and after antimicrobial therapy: use of conventional culture and polymerase chain reaction.

Antimicrobial therapy can increase the colonization density of gastrointestinal vancomycin-resistant enterococci (VRE). Among previously VRE-colonized patients, we evaluated VRE colonization before and after initiation of antimicrobial therapy by means of polymerase chain reaction (PCR) and culture. Perianal swab samples were obtained at admission to the hospital and after receipt of antimicrobial therapy. At admission, 12 (21%) of 56 patients were culture positive, and 17 (30%) had vanA or vanB genes detected by PCR. Culture results showed that 25 (86%) of 29 culture-negative patients from whom a second swab sample was obtained remained culture negative, 2 (6.9%) had a relapse of colonization with a strain related to the previously colonizing strain type (2 and 6 days after admission), and 2 (6.9%) tested positive for a previously undetected strain type (16 and 19 days after admission). PCR at admission detected VRE in 1 of the 2 patients who later relapsed. Patients with negative results of culture of the initial swab sample and of PCR were unlikely to relapse after receipt of antimicrobial therapy.

Left-sided endocarditis caused by Pseudomonas aeruginosa: successful treatment with meropenem and tobramycin.

Medical treatment alone is rarely successful in left-sided infective endocarditis caused by Pseudomonas aeruginosa. We report the cure of such a case with high-dose meropenem in combination with tobramycin.

Evaluation of the Vitek 2 system for rapid identification of clinical isolates of gram-negative bacilli and members of the family Streptococcaceae.

Accuracy of the Vitek 2 automated system (bioMérieux Vitek, USA) for rapid identification of bacteria was evaluated using a collection of 858 epidemiologically unrelated gram-negative and 99 gram-positive clinical isolates. Isolates were tested after subculturing to ensure purity. Conventional agar-based biochemical tests (Steers replicator) were used as a reference method of identification. Gram-negative bacteria were identified to the species level with 95.3% accuracy by the system ( Enterobacteriaceae, 95.9%; and non- Enterobacteriaceae, 92.5%), and gram-positive isolates with 72% accuracy. Although Vitek 2 identified routine clinical isolates of gram-negative bacilli and Enterococcus faecalis and Enterococcus faecium reliably, rapidly, and reproducibly, improvement is required in the identification of less common species of enterococci and viridans group streptococci.

Short-term oral estrogen replacement therapy does not augment endothelium-independent myocardial perfusion in postmenopausal women.

OBJECTIVES: The purpose of this study was to determine the effect of usual-dose estrogen replacement therapy (ERT) on myocardial perfusion and myocardial perfusion reserve (MPR) (evoked by an endothelium-independent vasodilator) in healthy postmenopausal women. Postmenopausal women have a decreased myocardial perfusion reserve compared with younger women. Estrogen infusions are known to enhance endothelium-dependent vasodilation of the epicardial coronary arteries in postmenopausal women, but whether ERT also enhances endothelium-independent myocardial perfusion and perfusion reserve is unclear. METHODS: In 24 healthy postmenopausal women who were not taking ERT, myocardial perfusion at rest, perfusion during the infusion of adenosine (a primarily endothelium-independent vasodilator), and MPR were determined by positron-emission tomography (PET) and oxygen 15-labeled water. The women were then randomly assigned in a double-blind fashion to receive either 0.625 mg of oral conjugated estrogens (Premarin) or placebo per day for 4 to 6 weeks, after which they underwent a repeat cardiac PET study. RESULTS: There was no statistical difference between those assigned to ERT and those assigned to placebo in the measurement of myocardial perfusion at rest (1.21 +/- 0.31 vs 1.16 +/- 0.18 mL/g/min, respectively) in response to adenosine (2.66 +/- 0.96 vs 3.3 +/- 0.45 mL/g/min) or MPR (2.24 +/- 0.83 vs 2.88 +/- 0.64 mL/g/min) after 4 to 6 weeks of oral ERT. There was also no difference between the groups in any of the myocardial perfusion measurements after correction for the rate-pressure product. CONCLUSIONS: Short-term oral ERT does not affect myocardial perfusion at rest in response to adenosine or MPR in healthy postmenopausal women. Thus potential beneficial effects of ERT on vasomotor function may be limited to enhancement of endothelium-dependent vasodilative mechanisms affecting conduit vessels.

Contamination of the clinical microbiology laboratory with vancomycin-resistant enterococci and multidrug- resistant Enterobacteriaceae: implications for hospital and laboratory workers.

We surveyed environmental surfaces in our clinical microbiology laboratory to determine the prevalence of vancomycin-resistant enterococci (VRE) and multidrug-resistant Enterobacteriaceae (MDRE) during a routine working day. From a total of 193 surfaces, VRE were present on 20 (10%) and MDRE were present on 4 (2%) of the surfaces tested. In a subsequent survey after routine cleaning, all of the 24 prior positive surfaces were found to be negative. Thus, those in the laboratory should recognize that many surfaces may be contaminated by resistant organisms during routine processing of patient specimens.

Fatal pseudomembranous colitis associated with a variant clostridium difficile strain not detected by toxin A immunoassay.

BACKGROUND: Many clinical laboratories use toxin A immunoassays to test for Clostridium difficile. OBJECTIVE: To describe the clinical course of a patient infected with a toxin variant strain of C. difficile that was not detected by toxin A immunoassay; to genetically characterize this strain; and to estimate the number of laboratories that use only toxin A immunoassays. DESIGN: Case report, molecular investigation, and laboratory survey. SETTING: Tertiary care hospital in Chicago, Illinois. PATIENT: An 86-year-old man. MEASUREMENTS: Restriction endonuclease analysis, polymerase chain reaction, and survey of regional clinical laboratories. RESULTS: An elderly hospitalized man died of advanced pseudomembranous colitis. Four stool specimens submitted over a 2-month period had tested negative on toxin A immunoassay, but a strain of C. difficile with a 1.8-kb deletion of the toxin A gene was recovered from each specimen. This strain, identified as restriction endonuclease analysis type CF4, is closely related to a widely disseminated variant, toxinotype VIII. Toxin A immunoassay was the only test being performed for detection of C. difficile at 31 of 67 (46%) regional clinical laboratories. CONCLUSIONS: Toxin A variant strains of C. difficile cause serious disease and are undetectable in clinical laboratories that use only toxin A immunoassays for C. difficile testing.

Quinolone molecular structure-activity relationships: what we have learned about improving antimicrobial activity.

Recently, understanding of how molecular modifications of the core quinolone structure affect(s) antimicrobial agent activity has progressed rapidly. Three positions (2, 3, and 4) cannot be changed without a significant loss of biological activity. Furthermore, it appears that a cyclopropyl group is optimal at position 1. Substituents at positions 5 and 8 affect planar configuration, and either a methyl or methoxy appear optimal at these sites. Hydrogen and amino groups have been investigated as useful substituents at position 6, replacing the fluorine of the fluoroquinolones. Interestingly, in vitro activity enhancement observed with alterations at positions 5 and 6 is not always accompanied by improved in vivo action. For all these modifications, the substituents at positions 7 and 8 are critical for potent antimicrobial activity. Optimizing overall molecular configuration enhances the number of intracellular targets for antimicrobial action (R-8) and impedes the efficiency of efflux proteins (R-7) that diminish intracellular penetration.

Fluoroquinolone resistance is a poor surrogate marker for type II topoisomerase mutations in clinical isolates of Streptococcus pneumoniae.

The association between fluoroquinolone susceptibility and DNA mutations coding for amino acid substitutions in the quinolone resistance-determining region was assessed with 44 clinical isolates of Streptococcus pneumoniae. Twenty-three strains bore at least one amino acid substitution. Only seven strains with mutations were suggested by diminished susceptibility to ciprofloxacin (MIC, > or =2 microg/ml).

Resistance to linezolid: characterization of mutations in rRNA and comparison of their occurrences in vancomycin-resistant enterococci.

To assess the potential for emergence of resistance during the use of linezolid, we tested 10 clinical isolates of vancomycin-resistant enterococci (VRE) (four Enterococcus faecalis, five Enterococcus faecium, and one Enterococcus gallinarum) as well as a vancomycin-susceptible control (ATCC 29212) strain of E. faecalis. The enterococci were exposed to doubling dilutions of linezolid for 12 passes. After the final passage, the linezolid plate growing VRE contained a higher drug concentration with E. faecalis than with E. faecium. DNA sequencing of the 23S rRNA genes revealed that linezolid resistance in three E. faecalis isolates was associated with a guanine to uracil transversion at bp 2576, while the one E. faecium isolate for which the MIC was 16 microg/ml contained a guanine to adenine transition at bp 2505.

New technology for detecting multidrug-resistant pathogens in the clinical microbiology laboratory.

Northwestern Memorial Hospital instituted in-house molecular typing to rapidly assess microbial clonality and integrated this typing into an infection control program. We compared data on nosocomial infections collected during 24 months before and 60 months after implementing the new program. During the intervention period, infections per 1,000 patient-days fell 13% (p=0.002) and the percentage of hospitalized patients with nosocomial infections decreased 23% (p=0.000006). In our hospital, the percentage of patients with nosocomial infections is 43% below the U.S. rate. Our typing laboratory costs approximately $400,000 per year, a savings of $5.00 for each dollar spent.

Engineering infection control through facility design.

Many medical centers have modified their facility design to provide a safer environment for patients. From an infection control perspective, the primary objective of hospital design is to place the patient at no risk for infection while hospitalized. We describe historical landmarks about hospital design, modern facility design, and specific designs to prevent acquisition and spread of infections such as tuberculosis and aspergillosis.

Low Prevalence of Community-Acquired Methicillin-Resistant Staphylococcus aureus in Adults at a University Hospital in the Central United States.

Community-acquired MRSA (CA-MRSA) is potentially a new emerging pathogen with most strains susceptible to many antimicrobials except for beta-lactam antibiotics. We retrospectively reviewed MRSA isolates during a 20-month study period (January 1998 through August 1999) and investigated those that were clindamycin susceptible. Patients were not considered to harbor CA-MRSA if they had been admitted to a hospital within the preceding 2 years or if their isolate had been obtained more than 72 h after admission. There were 2,817 S. aureus isolates, with 1,071 (38%) being MRSA. Of these 1,071 isolates, 161 were clindamycin susceptible; these were recovered from 81 patients. Of these 81 patients, 20 appeared to have community-acquired strains, but only 2 could be confirmed as having CA-MRSA.

Paenibacillus macerans pseudobacteremia resulting from contaminated blood culture bottles in a neonatal intensive care unit.

Paenibacillus species are gram-positive, rod-shaped, spore-forming aerobes that are abundant in nature and closely related to Bacillus. Between June 24 and June 30, 1999, 8 neonates in our neonatal intensive care unit had positive blood cultures for Paenibacillus macerans. This cluster of positive blood cultures with an unusual pathogen suggested a pseudoepidemic. Investigation revealed that the most likely etiology of the pseudobacteremia was environmental contamination of the rubber stoppers in blood culture bottles. This was confirmed by environmental sampling and simulated inoculation studies. This pseudobacteremia outbreak highlights the importance of adhering to well-established methods for blood culture collection and ongoing infection control surveillance.

Yield of vancomycin-resistant enterococci and multidrug-resistant Enterobacteriaceae from stools submitted for Clostridium difficile testing compared to results from a focused surveillance program.

It has been suggested that a method of performing surveillance for vancomycin-resistant enterococci (VRE) is to screen specimens submitted for Clostridium difficile testing. We compared this approach to our focused surveillance program of high-risk units during October 1997 to compare the yield of VRE and multidrug-resistant Enterobacteriaceae (MDRE) with both methods. Of the stools submitted for C. difficile testing, 14% were positive for VRE or MDRE, whereas rectal swabs from routine surveillance yielded 11% VRE- or MDRE-positive results. Although stools submitted for C. difficile testing resulted in a higher percentage of positive cultures, 14 VRE- and 2 MDRE-positive patients from our high-risk population were missed because many patients had no stool submitted for C. difficile testing. Therefore, while screening stools submitted for C. difficile testing cannot replace our focused surveillance program, it appears advantageous to assess these stools at various intervals to detect new patient reservoirs of drug-resistant organisms that may benefit from routine surveillance cultures.