Antimicrobial resistance (AMR) nanomachines: mechanisms for fluoroquinolone and glycopeptide recognition, efflux and/or deactivation

In this review, we discuss mechanisms of resistance identified in bacterial agents Staphylococcus aureus and the enterococci towards two priority classes of antibiotics—the fluoroquinolones and the glycopeptides. Members of both classes interact with a number of components in the cells of these bacteria, so the cellular targets are also considered. Fluoroquinolone resistance mechanisms include efflux pumps (MepA, NorA, NorB, NorC, MdeA, LmrS or SdrM in S. aureus and EfmA or EfrAB in the enterococci) for removal of fluoroquinolone from the intracellular environment of bacterial cells and/or protection of the gyrase and topoisomerase IV target sites in Enterococcus faecalis by Qnr-like proteins. Expression of efflux systems is regulated by GntR-like (S. aureus NorG), MarR-like (MgrA, MepR) regulators or a two-component signal transduction system (TCS) (S. aureus ArlSR). Resistance to the glycopeptide antibiotic teicoplanin occurs via efflux regulated by the TcaR regulator in S. aureus. Resistance to vancomycin occurs through modification of the D-Ala-D-Ala target in the cell wall peptidoglycan and removal of high affinity precursors, or by target protection via cell wall thickening. Of the six Van resistance types (VanA-E, VanG), the VanA resistance type is considered in this review, including its regulation by the VanSR TCS. We describe the recent application of biophysical approaches such as the hydrodynamic technique of analytical ultracentrifugation and circular dichroism spectroscopy to identify the possible molecular effector of the VanS receptor that activates expression of the Van resistance genes; both approaches demonstrated that vancomycin interacts with VanS, suggesting that vancomycin itself (or vancomycin with an accessory factor) may be an effector of vancomycin resistance. With 16 and 19 proteins or protein complexes involved in fluoroquinolone and glycopeptide resistances, respectively, and the complexities of bacterial sensing mechanisms that trigger and regulate a wide variety of possible resistance mechanisms, we propose that these antimicrobial resistance mechanisms might be considered complex ‘nanomachines’ that drive survival of bacterial cells in antibiotic environments

The challenge of curbing aminoglycoside resistance: can antimicrobial stewardship programs play a critical role?

Introduction: Aminoglycosides are useful antimicrobials, primarily for serious infections involving aerobic gram-negative pathogens. The inevitable increase in aminoglycoside resistance has led to calls for reducing levels of inappropriate aminoglycoside prescribing through the implementation of various antibiotic stewardship programs (ASPs). These programs mainly include restriction policies and aminoglycoside cycling. Although aminoglycoside resistance rates appear essential for measuring effectiveness of these interventions, most studies have focused on economic outcomes or clinical efficacy and toxicities. Areas covered: In the present study we estimated through a systematic literature review, the impact of early cycling studies and ASPs to aminoglycoside resistance rates for gram-negative pathogens. Expert commentary: Most ASPs support a positive association between aminoglycoside control policies and decrease of resistance rates. However, factors associated with aminoglycoside resistance are complex and multifactorial making it difficult to attribute resistance changes to a specific intervention. Optimized, high-dose, extended-interval aminoglycoside dosing and subsequent dosage monitoring by means of area under the curve and Cmax estimation, seem the most important strategies to improve clinical outcome, minimize toxicity and diminish resistance. The role of the clinical laboratory, using rapid and advanced assays and involved in pharmacodynamic target achievements, is also crucial to enable individualized or tailored aminoglycoside therapy. Future ASPs will need to combine high-quality epidemiological tools, novel diagnostic approaches and effective infection control measures. © 2017 Informa UK Limited, trading as Taylor & Francis Group

The Impact of Antibiotic Stewardship Programs in Combating Quinolone Resistance: A Systematic Review and Recommendations for More Efficient Interventions

Quinolones are among the most commonly prescribed antibiotics worldwide. A clear relationship has been demonstrated between excessive quinolone use and the steady increase in the incidence of quinolone-resistant bacterial pathogens, both in hospital and community sites. In addition, exposure to quinolones has been associated with colonization and infection with healthcare-associated pathogens such as methicillin-resistant Staphylococcus aureus and Clostridium difficile in hospitalized patients. Therefore, the management of quinolone prescribing in hospitals through antibiotic stewardship programs is considered crucial. Although suggestions have been made by previous studies on the positive impact of stewardship programs concerning the emergence and spread of multidrug-resistant bacteria at hospital level, the association of quinolone-targeted interventions with reduction of quinolone resistance is vague. The purpose of this article was to evaluate the impact of stewardship interventions on quinolone resistance rates and healthcare-associated infections, through a literature review using systematic methods to identify and select the appropriate studies. Recommendations for improvements in quinolone-targeted stewardship programs are also proposed. Efforts in battling quinolone resistance should combine various interventions such as restriction formulary policies, prospective audits with feedback to prescribers, infection prevention and control measures, prompt detection of low-level resistance, educational programs, and guidelines for optimal quinolone usage. However, the effectiveness of such strategies should be assessed by properly designed and conducted clinical trials. Finally, novel approaches in diagnostic stewardship for rapidly detecting bacterial resistance, including PCR-based techniques, mass spectrometry, microarrays, and whole-genome sequencing as well as the prompt investigation on the clonality of quinolone-resistant strains, will strengthen our ability to personalize quinolone prescribing to individual patients. © 2017, Springer Healthcare

Ambulatory blood pressure monitoring and target organ damage: Effects of age and sex

OBJECTIVE: The objective of the present study was to investigate the effect of age and sex in the ambulatory blood pressure measurements, and target organ damage. METHODS: A total of 1596 patients (50.6% male and 49.4% female), aged 10-87 years, referred to our Hypertension Center for borderline hypertension, underwent 24-h ambulatory blood pressure monitoring, left ventricular echocardiography and measurement of intima-media thickness of carotid arteries. RESULTS: Adolescent girls had higher mean 24-h and clinic systolic and diastolic blood pressure values than adolescent boys. Men aged 20-60 years had higher mean 24-h and clinic systolic and diastolic blood pressure values than women of the same age. Men older than 60 years had higher mean 24-h systolic and diastolic blood pressure values than women of the same age, but women older than 60 years had higher clinic systolic and diastolic blood pressure values. White-coat effect increased with age in both sexes, but the magnitude of the white-coat effect was higher in women than in men at older ages. Men had higher left ventricular mass corrected for body surface area or height than women in all ages and significantly higher differences in ages between 30 and 80 years. In addition, men had greater carotid intima-media thickness than women in all ages and significantly higher differences in ages between 30 and 80 years. CONCLUSIONS: Men have greater ambulatory blood pressure values and target organ damage than women of the same age. © 2006 Lippincott Williams & Wilkins

Impact of gender on 24-h ambulatory blood pressure and target organ damage

Differences between male and female subjects in mean 24 h blood pressure (BP) values and target organ damage such as left ventricular mass (LVMASS) and intima-media thickness (IMT) of carotid arteries were explained. The study population consisted of 1445 subjects. All subjects underwent 24 h ambulatory BP monitoring, left ventricular echocardiography and measurement of IMT of carotid arteries. Men and women did not differ in age, body mass index (BMI) and clinic BP values. Mean 24 h systolic and diastolic BP were significantly higher in men compared to women. LVMASS corrected for body surface area or height2.7, IMT of common (MCCA) and internal (MICA) carotid arteries were found to be significantly higher in men compared to women. Analysis of covariance showed that men had significantly higher LVMASS, MCCA and MICA than women, after adjustment for BMI, age, smoking status, mean 24 h systolic and diastolic BPs, fasting serum glucose, total cholesterol and triglycerides. These findings indicate that male sex could be an important predictor of higher mean 24 h BP and target organ damage for subjects of similar BMI and clinic BP values

Soil contamination by Toxocara canis and human seroprevalence in the Attica region, Greece

Background Toxocara canis is one of the most widespread public health and economically important zoonotic parasitic infections humans share with canids, mainly dogs. Human infection occurs by the accidental ingestion of embryonated eggs or larvae from a range of wild and domestic paratenic hosts. The aim of the present study was to examine the soil contamination of public places by the parasitic ova and to estimate serologically the prevalence of T. canis human infection in the Attica region, Greece. Methods In this region, public areas are permanently inhabited by dogs, mostly stray dog population that is hardly kept down to a manageable level. A total of 1,510 soil samples were collected from 33 public places of six regional units of Attica from March 2014 to April 2014 and ova were detected using a microscopic assay. In addition, sera were collected from 250 residents, routinely active in the sampled areas, and tested for T. canis IgG antibodies using an enzyme immunoassay. Results T. canis eggs were isolated from 31 (94%) of the examined public areas. Of the total samples, T. canis ova were recovered from 258 samples, suggesting an overall T. canis ova contamination of 17.2%. The areas of higher socioeconomic status presented lower percentages of soil contamination in a statistically significant level, compared to the areas of lower socioeconomic status. T. canis IgG seropositivity was detected in 40 (16%) serum samples. Similar rates were established among T. canis seropositivity and soil contamination within the same geographical areas. The proportion of seropositive samples in the group of children was significantly higher compared to the proportion of adults (48% versus 8%, p<0.001). Conclusion The level of environmental T. canis contamination as well as human infection found in the Attika region calls for a greater awareness towards this public issue. Preventing measures should be implemented to control the spread of this parasitic infection. © GERMS 2018

Chlamydia trachomatis serovar distribution and Neisseria gonorrhoeae coinfection in male patients with urethritis in Greece

The distribution of Chlamydia trachomatis serovars and Neisseria gonorrhoeae coinfection was studied in a group of 100 C. trachomatis-positive males with urethritis in Greece. The serovar distribution revealed that apart from the predominant worldwide types E and F, the relatively uncommon type G is also prevalent. Gonococcal coinfection was frequent (30%) and was associated with genovariant Ja (75%, P = 0.008). Copyright © 2010, American Society for Microbiology. All Rights Reserved

Antimicrobial stewardship program in a Greek hospital: Implementing a mandatory prescription form and prospective audits

Aim: Antimicrobial stewardship programs (ASPs) are urgently needed for Greek hospitals in order to improve antibiotic usage. Patients & methods: An ASP was implemented to a Greek hospital since February 2014. A mandatory order form was introduced for five antimicrobials; colistin, tigecycline, daptomycin, doripenem and linezolid. Prospective audits allowed for feedback to the prescribers without direct prescribing restriction. Results: Antimicrobials' consumption at the baseline year and the 3 years of ASP implementation was 93.7, 99.1, 156.1 and 105.9 defined daily doses/1000 patient days, respectively (p > 0.05). No statistically significant difference in isolation rates of multidrug-resistant pathogens was detected. Conclusion: Efforts are required to demonstrate the long-term impact of our program on antibiotic prescription attitudes as well as antimicrobial resistance rates. © 2018 Future Medicine Ltd

Hypertension and hypothyroidism: Results from an ambulatory blood pressure monitoring study

OBJECTIVE: To examine differences between hypothyroid patients and healthy volunteers in 24-h ambulatory blood pressure parameters. METHODS: The study population consisted of 100 individuals who were recently diagnosed for hypothyroidism. These patients had never been treated before with antihypertensive treatment or received drugs for hypothyroidism. All participants underwent 24-h ambulatory blood pressure monitoring. The control group consisted of 100 healthy volunteers matched one to one for gender and age with the hypothyroid participants. RESULTS: Clinic systolic and diastolic blood pressures were significantly higher in patients with hypothyroidism compared with volunteers. The mean 24-h systolic blood pressure and 24-h pulse pressure were significantly higher in patients with hypothyroidism compared with volunteers. The 24-h systolic blood pressure variability was also significantly higher in patients with hypothyroidism. Fasting serum cholesterol tended to be higher in patients with hypothyroidism compared with volunteers but the difference was not statistically significant, while fasting serum triglycerides were significantly higher. Body mass index was also significantly higher in patients with hypothyroidism. CONCLUSIONS: These findings indicate that hypothyroidism may be an important predictor of higher mean 24-h systolic blood pressure, 24-h pulse pressure and 24-h systolic blood pressure variability, parameters of ambulatory blood pressure monitoring that have been previously associated with higher cardiovascular target organ damage. © 2007 Lippincott Williams & Wilkins, Inc

Trends in antimicrobial resistance of clinical isolates of Enterococcus faecalis and Enterococcus faecium in Greece between 2002 and 2007

We analysed trends in antimicrobial resistance of Enterococcus faecalis (N=1498) and E. faecium (N=625) recovered from clinical infections during 2002-2007 in a Greek tertiary care hospital. Molecular assays were used to confirm speciation and genotype of vancomycin-resistant enterococci (VRE). The incidence of infections per 1000 admissions caused by E. faecalis and E. faecium increased during the study period (χ2 for trend=25.5 and 13.3, respectively; P<0.0001). Resistance to ampicillin, high level gentamicin and streptomycin, vancomycin, teicoplanin and linezolid was found in E. faecalis/E. faecium at rates of 1.3/82.4%, 45.6/51.2%, 48.9/69.1%, 0.5/9.6%, 0.1/8.2% and 0.3/1.6%, respectively. The vanA gene was identified in 79.1% of the VRE isolates, with vanB found in the remaining 20.1%. Analysis of antimicrobial resistance trends showed consistently high rates of ampicillin resistance among E. faecium isolates. For both enterococcal species, high level resistance to gentamicin and streptomycin were noted to have increased significantly (P<0.0001). Regardless of these alarming trends, strains exhibiting resistance to oxazolidinones seem to be only sporadic in our region and a trend toward increasing resistance rates to glycopeptides was not detected. © 2009 The Hospital Infection Society