How predictable is development of resistance after β-lactam therapy in Enterobacter cloacae infection?

Certain non-fastidious Gram-negative bacilli, notably Enterobacter cloacae, although classified as susceptible by usual in-vitro susceptibility testing, often become resistant in patients treated with newer β-lactam antibiotics. Here various in-vitro tests were carried out together with an animal model allowing the quantification of resistance that emerges after short term therapy. Mice were challenged (102 cfu plus talcum) intraperitoneally with one each of four strains of Ent. cloacae. Two hours later, a single β-lactam dose was administered subcutaneously. The following day, the peritoneal bacterial population was analysed by using antibiotic-containing gradient plates. Development of resistance after therapy varied according to the compound considered. Imipenem (50 mg/kg) produced no resistance, and piperacillin (200 mg/kg) only a few, while resistance occurred frequently after therapy with aztreonam (50 mg/kg), ceftazidime (50 mg/kg), cefotaxime (50 mg/kg) and cefpirome (50 mg/kg). MICs increased by at least 16-fold when resistance developed. No simple correlations were found between these in-vivo results and initial MICs, killing kinetics, frequency of resistant variants within the bacterial populations before therapy, initial MIC of these variants or antibiotic concentrations assayed in peritoneal fluid 60 min after dosing. The most reliable predictive in-vitro test appeared to be the determination of resistance emerging in broth containing at least 16 times the MIC of the antibiotic tested. Such a test is unlikely to be used on a routine basis. When a β-lactam compound seems appropriate for treating an Enterobacter infection, it may be advisable to avoid drugs that are prone prone to produce resistance in experimental or clinical infections, whatever the results of conventional in-vitro susceptibility test

In-vitro activity of newer quinolones against aerobic bacteria

Nalidixic and five newer 4-quinolones, ciprofloxacin, enoxacin, norfloxacin, ofloxacin and pefloxacin were tested against 576 recent clinical aerobic bacterial isolates. The 4-quinolones were regularly active (MIC90 < 4 mg/1) against the following bacteria: Staphylococcus aureus, S. epidermidis, S. saprophyticus, different Enterobacteriaceae, Haemophilus influenzae, Campylobacter jejuni, Pseudomonas aeruginosa, Agrobacter spp., Aeromonas spp., Plesiomonas spp., Neisseria meningitidis. Other bacteria were usually intermediately susceptible or resistant: different streptococci, Listeria monocytogenes, Nocardia asteroides, P. maltophilia, Achromobacter xylosoxydans and Alcaligenes denitrificans. Ciprofloxacin was the most potent compound, followed by ofloxacin and pefloxacin, norfloxacin and enoxacin being less active. All the 4-quinolones were much more active than nalidixic acid. The MBC/MIC ratios of the 4-quinolones were between 1 and 2 with a majority of strains, and between 2 and 3 with Streptococcus agalactiae, Str. faecalis and L. monocytogenes. A two- to eight-fold increase of MIC was observed by increasing the inoculum 10,000-fold with most of the strains tested. Susceptible bacterial population of Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens and P. aeruginosa contained more clones resistant to nalidixic acid (104 to 108 at four times the MIC) than to 4-quinolones (105 to 109 at four times the MIC). Supplementing the media with MgSO4 produced smaller inhibition zone diameters with a disc diffusion method than those obtained with non-supplemented agar, with all quinolone or strains. Less regular effect, or no effect was obtained after supplementation with ZnSO4 or Ca(NO3)

Clinical determinants of adrenal vein sampling success

Background: Primary aldosteronism (PA) is one of the most prevalent forms of secondary hypertension, which may be cured by unilateral adrenalectomy. Adrenal vein sampling (AVS) is considered the gold-standard procedure for distinction between bilateral and unilateral aldosterone hypersecretion. However, the procedure is viewed as a technical challenge. The objectives of this study were to define the success rate of AVS, and its clinical determinants, and to compare the accuracy of high-resolution adrenal computed tomography (CT) with AVS. Methods: In this single-centre retrospective study, patients with biologically proven PA who were referred for AVS between 2009 and 2014 were included. Adrenal vein catheterisation was considered selective if the selectivity index (adrenal vein / inferior vena cava cortisol) was ≥2. Results: Data from 68 patients (48% women) were available. The success rate of catheterisation in bilateral AVS was 60% (41/68). The significant clinical determinants of success were male sex (r = 0.35, p = 0.004), a higher body mass index (BMI) (r = 0.54, p = 0.001) and plasma creatinine (r = 0.25, p = 0.048) in univariate analysis. In multivariate linear regression analysis, only BMI was associated with success (coefficient = 0.049, p = 0.004). CT was discordant with AVS in 53% of patients, and would have resulted in inappropriate adrenalectomy in 43% of the patients and inappropriate exclusion from surgery in 10% of the cases. Conclusion: Clinical characteristics such as BMI and sex may influence the success rate of AVS. The inaccuracy of CT may result in inappropriate treatment proposals if the indication for surgical intervention is based on CT only

Emergence of resistance after therapy with antibiotics used alone or combined in a marine model

A murine model of peritonitis allowing detection and quantification of in-vivo acquired resistance during short term therapy has been used in order to evaluate the capacity of antimicrobial combinations to limit emergence of resistance, as compared to individual components of the regimens. Mice were challenged intraperitoneally with 108 cfu of bacteria. Two hours later, a single antibiotic dose was injected subcutaneously: amikacin (15 mg/kg), ceftriaxone (50 mg/kg), pefloxacin (25 mg/kg), amikacin + ceftriaxone, amikacin + pefloxacin or ceftriaxone + pefloxacin. Escherichia coli and Staphylococcus aureus never became resistant. Single drug therapy yielded resistant mutants in Enterobacter cloacae, Serratia marcescens, Klebsiella pneumoniae and Pseudomonas aeruginosa as follows: 74% of ceftriaxone-treated animals, 57% of pefloxacin treated animals and 27% of amikacin treated animals. All the tested combinations reduced the frequency of in-vivo acquired resistance produced by single drugs, and no combination selected resistance when the separate agents of the combination did not. Combining antimicrobial agents limits the risk of emergence of resistance during antibiotic therap

Comparative in-vitro activity of new quinolones against clinical isolates and resistant mutants

The in-vitro activity of five new fluoroquinolones, WIN 57273, sparfloxacin, flerox-acin, temafloxacin and tiprofloxacin was determined against 543 recent clinical isolates and eight quinolone resistant strains derived by mutation and their five parent strains. WIN 57273 was the most active compound against Gram-positive bacteria, sparfloxacin had a broad spectrum which was similar to that of cipro-floxacin. Ciprofloxacin showed the greatest activity against Gram-negative bacteria. Temafloxacin showing some activity against Gram-positive organisms and Acinetobacter spp. Fleroxacin was the least active compound studied. Compared to wild type parent strains, the mutated strains produced the following results. In Enterobacter cloacae OmpF deficiency increased the MICs of all quinolones by 8-32-fold. In Pseudomonas aeruginosa OmpF deficiency had a limited effect, Omp D2 deficiency combined with an increased lipopolysaccharide content produced greater resistance, i.e. 4-16-fold; mutations in gyrase were associated with variously increased MICs, depending on the strain and compound teste

Blood pressure changes after renal denervation at 10 European expert centers

We did a subject-level meta-analysis of the changes (Δ) in blood pressure (BP) observed 3 and 6 months after renal denervation (RDN) at 10 European centers. Recruited patients (n=109; 46.8% women; mean age 58.2 years) had essential hypertension confirmed by ambulatory BP. From baseline to 6 months, treatment score declined slightly from 4.7 to 4.4 drugs per day. Systolic/diastolic BP fell by 17.6/7.1 mm Hg for office BP, and by 5.9/3.5, 6.2/3.4, and 4.4/2.5 mm Hg for 24-h, daytime and nighttime BP (P0.03 for all). In 47 patients with 3- and 6-month ambulatory measurements, systolic BP did not change between these two time points (P0.08). Normalization was a systolic BP of &#60;140 mm Hg on office measurement or &#60;130 mm Hg on 24-h monitoring and improvement was a fall of 10 mm Hg, irrespective of measurement technique. For office BP, at 6 months, normalization, improvement or no decrease occurred in 22.9, 59.6 and 22.9% of patients, respectively; for 24-h BP, these proportions were 14.7, 31.2 and 34.9%, respectively. Higher baseline BP predicted greater BP fall at follow-up; higher baseline serum creatinine was associated with lower probability of improvement of 24-h BP (odds ratio for 20-μmol l(-1) increase, 0.60; P=0.05) and higher probability of experiencing no BP decrease (OR, 1.66; P=0.01). In conclusion, BP responses to RDN include regression-to-the-mean and remain to be consolidated in randomized trials based on ambulatory BP monitoring. For now, RDN should remain the last resort in patients in whom all other ways to control BP failed, and it must be cautiously used in patients with renal impairment

Relation of 24-hour urinary caffeine and caffeine metabolite excretions with self-reported consumption of coffee and other caffeinated beverages in the general population.

Caffeine intake is generally estimated by self-reported consumption, but it remains unclear how well self-report associates with metabolite urinary excretion. We investigated the associations of self-reported consumption of caffeinated drinks with urinary excretion of caffeine and its major metabolites in an adult population. We used data from the population-based Swiss Kidney Project on Genes in Hypertension (SKIPOGH) study. Consumption of caffeinated coffee, decaffeinated coffee and other caffeinated beverages was assessed by self-administered questionnaire. Quantification of caffeine, paraxanthine, theobromine and theophylline was performed by ultra-high performance liquid chromatography tandem mass spectrometry in 24-h urine. Association of reported consumption of caffeinated drinks with urinary caffeine derived metabolites was determined by quantile regression. We then explored the association between urinary metabolite excretion and dichotomized weekly consumption frequency of caffeinated coffee, with Receiver Operator Characteristic (ROC) analysis. In the present analysis, we included 598 individuals (52% women, mean age =46 ± 17 years). Self-reported caffeinated coffee intake was positively associated with 24-h urinary excretions of paraxanthine, theophylline and caffeine (p &lt; 0.001), whereas reported intakes of decaffeinated coffee and other caffeinated beverages showed no association. In ROC analysis, optimal discrimination between individuals consuming less than one caffeinated coffee/week, vs. at least one coffee, was obtained for 24-h urinary paraxanthine (Area Under Curve (AUC) = 0.868, 95% Confidence Interval (CI) [0.830;0.906]), with slightly lower performance for theophylline and caffeine, whereas theobromine did not allow any discrimination. Our results suggest that reported consumption of caffeinated coffee is positively associated with 24-h urinary excretion of caffeine, paraxanthine, and theophylline, and may be used as a marker of caffeine intake for epidemiological studies