[MULTIRESISTANT BACTERIA].

The most important multiresistant bacteria causing treatment failures are extended-spectrum ß-lactamase and/or plasmid-mediated AmpC ß-lactamase positive Enterobacteriaceae, carbapenemase producing Acinetobacter baumannii and Pseudomonas (P.) aeruginosa, methicillin-resistant Staphylococcus (S.) aureus, penicillin-resistant Streptococcus pneumoniae, and van-comycin- resistant Enterococcus spp. Extended-spectrum ß-lactamases hydrolyze oxyimino-caphalosporins and aztreonam, are mostly produced by Enterobacteriaceae, and are encoded on transferable plasmids which often contain resistance genes to non-ô€ -lactam antibiotics. Plasmid-mediated AmpC ß-lactamases descend from the chromosomal ampC gene transferred to the plasmid. Those ô€ -lactamases confer resistance to first, second and third generation of cephalosporins, monobactams, and to ô€ -lactam-ô€ -lactamase inhibitor combinations. Enterobacteriaceae may develop resistance to carbapenems due to the hyperproduction of ESBLs or plasmid-mediated AmpC ß-lactamases in combination with porin loss or due to the production of carbapenemases of class A (KPC, IMI, NMC, SME), B (metallo-ß-lactamases from VIM, IMP or NDM series), and D (OXA-48 ß-lactamase). Carbapenemases found in Acinetobacter spp. belong to molecular class A (KPC), B (metallo-ß-lactamases of IMP, VIM, NDM or SIM family) and D (OXA enzymes). The most frequent mechanism of carbapenem resistance in Acinetobacter spp. is through the production of OXA-enzymes but other various mechanisms including decreased permeability and efflux pump overexpression could also be involved. Carbapenem-resistance in P. aeruginosa is usually mediated by the production of metallo-ß-lactamases of IMP, VIM, GIM, SPM or NDM series, loss of OprD outer membrane protein and/or upregulation of MexAB or MexCD efflux pumps. Methicillin-resistance in S. aureus occurs as the result of the acquisition of mecA gene that encodes novel PBP2a protein. Expression of PBP2a renders bacteria resistant to all ô€ -lactams including cephalosporins (with the exception of ceftaroline and ceftobiprole) and carbapenems. Most strains of penicillin resistant Streptococcus pneumoniae are often resistant to cephalosporins and antibiotics from other classes, presenting a serious problem in treating invasive infections. The most important therapeutic problem in enterococci is development of resistance to vancomycin.

Diversity of carbapenemases in clinical isolates of Enterobacteriaceae in Croatia--the results of a multicentre study.

Since the first carbapenem-resistant Klebsiella pneumoniae strain was isolated in 2008, Enterobacteriaceae with reduced susceptibility to one or more carbapenems have emerged sporadically in different geographical regions in Croatia. These observations gave rise to a multicenter study on carbapenem resistance in Enterobacteriaceae from Croatia. Fifty-seven carbapenem-non-susceptible strains of Enterobacteriaceae were collected during 2011-2012 from four large hospital centres in Croatia. Overall, 36 strains produced VIM-1 ß-lactamase, three produced NDM-1, and one produced KPC-2. A high degree of clonal relatedness was observed in Enterobacter cloacae and Citrobacter freundii strains, in contrast to K. pneumoniae strains. BlaVIM genes were located within class1 integron which contained genes encoding resistance to aminoglycosides (aacA4 ). The study found strong association between blaVIM and qnrB6 and between blaNDM and qnrA6 genes.

Diuretic effects of furosemide infusion versus bolus injection in congestive heart failure.

In a randomized, single-blind, crossover clinical trial, the diuretic efficacy of the same total dose of furosemide (2 x 40 mg) administered in either conventional intravenous bolus injection or continuous infusion was studied in 20 patients (nine males and 11 females), aged 37-75 years, with congestive heart failure. Furosemide infusion, administered first, produced a significantly greater diuresis than the bolus when compared with baseline (86%: 29.6%; p = 0.029). This was followed by a similar increase in 24-h urinary sodium, potassium and chloride excretion, with no significant difference from the bolus effect. The following day, diuretic and saluretic effects of furosemide did not differ significantly between the study groups. Nevertheless, when continuous furosemide infusion was administered first, it produced a greater increase in urinary volume, 24-h urinary sodium, potassium and chloride than when bolus injection was applied the next day. Conversely, when furosemide bolus was administered first, followed by the infusions the next day, the effects were almost equal, regardless of the mode of administration. It is concluded that in the treatment of refractory edema in patients with congestive heart failure, continuous intravenous infusion of furosemide is superior to the conventional intermittent bolus injection, especially if it is administered at the very beginning of the hospital treatment, and presumably is even better with higher dosage and longer infusion time span.

Comparison of chlorthalidone, propranolol and bopindolol in six-month treatment of arterial hypertension.

The aim of this study was to test the hypothesis that prolonged treatment of mild to moderate hypertension with low-dose thiazide diuretics or beta blockers does not induce any of the major untoward biochemical changes, such as hypertriglyceridemia, hypercholesterolemia, hyperuricemia and electrolyte imbalances. The effect of these drugs was analyzed in 100 outpatients (52 males and 48 females) aged 52.0 +/- 7.9 years with mild to moderate hypertension, in a prospective 6-month study. After an appropriate workup, the patients were randomized to either 25 mg chlorthalidone (40 patients), 120 mg propranolol (30 patients), or 2 mg per day bopindolol (30 patients). A significant reduction of approximately 10% in systolic and diastolic blood pressure was recorded in all the groups. At the end of the 6th month, in the chlorthalidone group triglycerides increased to 3.0 +/- 2.1 mmol/l from 2.8 +/- 1.6 mmol/l, while cholesterol after an initial increase to 6.6 +/- 1.6 from 6.4 +/- 1.6 mmol/l returned to the baseline level. Uricemia and serum potassium concentration decreased by 4%. The body weight was reduced to 83.8 +/- 13.4 kg from 86.1 +/- 13.4 kg. There was no change in serum glucose level. In the propranolol group, as expected, heart rate decreased by 20%, but there were no significant changes in glucose and potassium plasma concentration. Triglycerides did not change significantly, while cholesterol, after a small increase, returned to the initial levels. Similar results were obtained in the bopindolol group, apart from the triglycerides, which increased significantly (to 2.5 +/- 1.1 from 2.2 +/- 0.4 mmol/l), probably because of the lower baseline concentration. We conclude that in prolonged treatment, chlorthalidone, propranolol and bopindolol do not induce significant untoward biochemical changes that alone might increase cardiovascular risk.

QT interval as a marker of venous reactivity in dialysis patients.

Fourteen patients (7 females and 7 males, mean age 51.9 +/- 11.6 years) were studied to find out whether there is a connection between the QTc interval (a diagnostic tool for evaluating autonomic neuropathy) and venous reactivity in uremics on chronic hemodialysis. The QT interval was measured using standard lead II as reference, corrected for heart rate, and designed QTc. Venous reactivity was measured by the so-called venoconstriction test. Pressure changes inside the vein were obtained by injection of 2 micrograms of noradrenaline, and expressed in venoconstrictive units (VCU). The mean QTc was 445.7 +/- 36.9 ms. The mean venous tone response was 2130.9 +/- 1435.5 VCU. There was a significant correlation between the QTc interval and venous reactivity to catecholamine (r = 0.565, P = 0.03). It is concluded that the QTc interval may be used as a marker of venous tone reactivity, suitable for everyday clinical practice. Furthermore, the magnitude of this reactivity possibly represents either the end-organ or peripheral sympathetic impairment.

Venous tone in glaucoma and hypertension.

The aim of this study was the assessment of physiological venous reflexes in systemically hypertensive and normotensive subjects with primary open-angle glaucoma. The experimental group consisted of 20 normotensive and 20 untreated systemically hypertensive patients with open-angle glaucoma. The control group consisted of 31 volunteers divided into two subgroups: 16 control normotensives and 15 untreated hypertensives. The assessment of venous tone changes was performed by testing venous reflexes. Venoconstriction responses to physiological stimuli were significantly decreased in normotensive glaucoma patients, compared to normotensive controls [for the Valsalva manoeuvre 93.4 +/- 80.2 vs. 413.3 +/- 335.4 venoconstrictive units (VCUs), p = 0.02, and for a deep breath 89.1 +/- 100.1 vs. 316.8 +/- 343.2 VCUs, p = 0.03]. The intensity of venous reflexes in hypertensive glaucoma patients did not differ significantly from that seen in hypertensive controls, due to a significantly weaker flex venoconstriction in hypertensive controls when compared to normotensive controls subjects. This study confirmed the presence of venous dysregulation in subjects with primary open-angle glaucoma and visual field loss as a part of an autonomic dysfunction. Systemic hypertension does not make this condition worse.

Venous reflex testing in glaucoma.

The aim of this study was the assessment of physiological venous reflexes in open angle glaucoma. The study was carried out by a controlled clinical experiment. The experimental group consisted of 17 glaucoma patients with controlled intraocular pressure. The control group consisted of 15 healthy volunteers. The assessment of venous tone changes was performed by means of the test of "venous reflexes". Venoconstriction responses to physiological stimuli were significantly decreased in glaucoma patients (p < 0.05). The results suggested venous dysregulation as part of sympathetic dysfunction in glaucoma.

[Biochemical changes in hypertensive patients during a 1-year cross-over study of treatment with hydrochlorothiazide and propranolol]. / Biokemijske promjene u hipertonicara tijekom jednogodisnjeg krizanog lijecenja hidroklorotiazidom i propranololom.

A prospective, randomized, cross-over trial comparing the antihypertensive efficacy and biochemical changes during treatment with either hydrochlorothiazide (HTZ: 25 mg o.d.) or propranolol (PRO: 40 mg t.i.d.), included 55 mild to moderate hypertensives (diastolic blood pressures ranged from 90 to 110 mmHg), aged 25-65 years. Forty patients completed the study; during the first six months 20 of them (12 males and 8 females) were taking HTZ, and the remaining 20 (13 males and 7 females) PRO. After a one-week wash-out period, for the next six months the alternative drug was administered. Antihypertensive efficacy of both drugs was nearly equal: systolic and diastolic blood pressure significantly decreased already after the first month (approximately by 10%), and kept unchanged until the end of the study. The analyzed biochemical parameters, i.e. blood glucose, cholesterol, and triglycerides did not increase significantly, while serum potassium level remained almost unchanged during the trial. Furthermore, during PRO in group B, cholesterol significantly decreased (3rd month), as well as blood glucose during HTZ treatment (10th month). Only the uric acid level, although unsignificantly, increased in group A (from 326.2 to 365.3 +/- 125.2 on HTZ, and to 391.4 +/- 120.0 mumol/l on PRO). It is concluded that HTZ and PRO are comparably effective antihypertensives. During the long-term treatment in small doses these drugs do not induce significant biochemical disturbances.

Ramipril decreases chlorthalidone-induced loss of magnesium and potassium in hypertensive patients.

A double-blind clinical trial was conducted to compare the efficacy of and electrolyte changes caused by ramipril-chlorthalidone combination treatment (5 mg + 25 mg) and chlorthalidone monotherapy (25 mg daily) in patients with hypertension. After a 4-week placebo period, 32 patients (mean age, 51 +/- 9 years) with essential hypertension (average blood pressure of 181.4/104.5 +/- 13.0/6.9 mmHg) were randomly assigned to receive combination therapy (group A, n = 17) or monotherapy (group B, n = 15). After 12 weeks of active treatment, systolic and diastolic blood pressure decreased by 16.1% and 13%, respectively, for patients taking combined therapy, and by 12.7% and 9.8%, respectively, for patients taking monotherapy. The difference was significant for between-group comparisons. There were no changes in serum sodium concentration, but a significant similar increase in 24-hour urinary sodium excretion was seen in both groups. Serum calcium levels increased slightly and 24-hour urinary calcium excretion decreased significantly in both groups, probably due to chlorthalidone administration. Serum potassium levels increased slightly in group A (from 4.16 +/- 0.39 mmol/L to 4.30 +/- 0.42 mmol/L) and decreased slightly in group B (from 4.18 +/- 0.32 mmol/L to 3.99 +/- 0.49 mmol/L). Urinary potassium excretion did not change significantly in group A, but increased by approximately 15% in group B. There was a decrease in 24-hour urinary magnesium excretion (from 4.01 +/- 1.24 mmol/24 hours to 3.50 +/- 0.93 mmol/24 hours) in group A and an increase (from 3.49 +/- 0.98 mmol/24 hours to 4.35 +/- 1.12 mmol/24 hours) in group B. At the end of the trial these changes were significant in between-group comparisons. Consistent with the previously shown amelioration by ramipril of thiazide-induced metabolic side-effects, ramipril appears to improve magnesium balance during cotreatment with chlorthalidone.

[The vasodilating effect of chlorthalidone in mild hypertension evaluated by impedance venous plethysmography]. / Vazodilatacijsko djelovanje klortalidona u blagih hipertonicara vrednovano zapornom venskom pletizmografijom.

Thirty hypertensive outpatients of both sexes having diastolic blood pressure below 110 mmHg were included in a randomized trial. Their mean age was 50.4 +/- 8.6 years. After a two-week placebo period, the patients were treated with chlorthalidone in a single daily dose of 25 or 12.5 mg over the one-month period, and the next month the alternative dose (i.e. 12.5 or 25 mg) was administered. Changes in vascular reactivity were measured by occlusive plethysmography (mercury strain-gauge) at the end of the placebo period, and then post the first and second month of therapy. All the observed parameters, i.e. rest flow (RF), peak flow (PF), venous capacity (VC), and maximal venous outflow (MVO) increased with 25 mg of chlorthalidone, and similar findings were registered when a dose of 12.5 mg was given. There was a significant increase in venous capacity of both groups (from 2.6 to 3.2 and from 3.0 to 3.4 ml/100/min) and in peak flow of the group that was on 25 mg of chlorthalidone as the first dose (from 18.6 to 23.9 ml/100ml/min). Both doses had similar antihypertensive effect. It is concluded that antihypertensive effect of chlorthalidone is partly due to changes in vascular reactivity in the sense of vasodilation which is more prominent at the venous side of the blood flow, Low-dosed chlorthalidone is equipotent in antihypertensive efficiency, its side effects are rare, and the cost of therapy is by far the lowest.

Vascular effects of chlorthalidone in mild hypertensives.

In a randomized trial with chlorthalidone, 30 hypertensive outpatients of both genders, aged 50.4 +/- 8.6 years, having diastolic blood pressure between 95 and 110 mm HG were divided into 2 groups of 15, after a two-week placebo period. The A group received chlorthalidone in a single dose of 23 mg for one month, and the next month was given a 12.5 mg alternative dose, whereas the B group was given 12.5 mg in the first month and 25 mg in the second. Changes in vascular reactivity were measured by occlusive plethysmography (mercury strain-gauge) at the ends of the placebo period, the first and the second month of therapy. All the observed parameters, i.e. rest flow, peak flow, venous capacity, and maximal venous outflow, were found to have increased with 25 mg chlorthalidone, and similar findings were registered when 12.5 mg of the drug were given. Venous capacity increased significantly in both groups (from 2.6 to 3.2 and from 3.0 to 3.4 ml/100 ml). The peak-flow values augmented significantly only in the group where 25 mg of chlorthalidone were given first (from 18.6 to 23.9 ml/100 ml/min). Both doses had a similar antihypertensive effect, decreasing the mean arterial pressure by some 8% in the upright, sitting, and supine position. It is concluded that the antihypertensive effect of chlorthalidone is, at least partly, due to changes in vascular reactivity; vasodilation is more prominent on the venous side of the circulation. Low-dose chlorthalidone is equipotent as antihypertensive, its side-effects are rare, and the cost of such a therapy is by far the lowest.

[Comparison of amlodipine and the nifedipine retard preparation in the treatment of arterial hypertension]. / Usporedba amlodipina i retard pripravaka nifedipina u lijecenju arterijske hipertenzije.

The efficacy and acceptability of amlodipine (5-10 mg o.d.) and sustained-release nifedipine (20-40 mg b.i.d.) were compared in a multicenter, double-blind clinical trial. After a two-week placebo period, 71 essential hypertensives of both sexes, aged 51.7 +/- 8.5 years, having diastolic blood pressure of 95-114 mmHg were randomly allocated to either amlodipine 5 mg once daily (group A) or nifedipine 20 mg twice daily (group B). With respect to the blood pressure response, the initial dose was doubled after two weeks. No significant differences in blood pressures recorded at baseline and at the end of the placebo period were demonstrated. A significant reduction in both systolic and diastolic blood pressures in the supine position was observed already two days after the start of treatment. In the group A it decreased from 163.2 +/- 21.4/102.7 +/- 8.5 to 155.7 +/- 20.7/98.2 +/- 8.9 mm Hg (p < 0.05) and in the group B from 160.5 +/- 16.2/100.5 +/- 12.2 to 152.2 +/- 17.0/95.4 +/- 9.5 mm Hg (p < 0.05). The similar changes of blood pressure were observed in the standing position, as well. At the end of the study, the overall reduction of the supine diastolic blood pressure was 12.5% in the group A versus 5.2% in the group B (p < 0.05). In the standing position, amlodipine decreased diastolic blood pressure by 8.8% and nifedipine by 6.4% (p < 0.05). Furthermore, amlodipine decreased the standing diastolic blood pressure to a greater extent (8.8% versus 6.4%; p < 0.05) than nifedipine.(ABSTRACT TRUNCATED AT 250 WORDS)

[Orthostatic hypotension. Case report of the Bradbury-Eggleston syndrome]. / Ortostatska hipotenzija. Prikaz slucaja Bradbury-Egglestonova sindroma.

A case of a 71-year-old woman with idiopathic orthostatic hypotension is presented. Several diagnostic procedures which can detect sympathetic pathway lesion are reported. The value of blood pressure measurement and heart rate response to the supine and standing position deep breath, Valsalva maneuver and cold pressor test in differential diagnosis are emphasized. The venoconstriction, venous reflexes and tyramine tests are described, as well. The authors favour an individual therapeutic approach with no limitation of mineralocorticoid dosage. Nonpharmacological measures, such as an increased salt intake, elastic support stockings and swimming are highly recommended.

[How much do we understand about pharmacotherapy of cardiac arrhythmias?]. / Koliko razumijemo farmakoterapiju srcanih aritmija?

By an anonymous, multiple-choice questionnaire assessed was the knowledge of cardiac electrophysiology and mechanism of action of some antiarrhythmic drugs among the staff members of a department of medicine from a large regional hospital. The overall results were disappointing (over 55 per cent of inaccurate answers), but improved after 3 months (less than 30 per cent). It is concluded that such a polling increases the level of awareness about target problem (cardiac arrhythmia management in the actual case) and improves the performance of health professionals.