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Background and purpose: Aspirin reduces the risk of myocardial infarction and stroke by inhibiting thromboxane production in platelets. This inhibition can be competitively antagonized by some non-steroidal anti-inflammatory drugs (NSAIDs). Experimental approach: By measuring thromboxane B2 production in healthy volunteers, we investigated whether ibuprofen (800 mg three times daily for 7 days) or diclofenac (50 mg three times daily for 7 days) taken concurrently with aspirin 80 mg (once daily for 7 days) influenced the inhibitory effect of aspirin. The effects were compared with aspirin 30 mg (once daily for 7 days), which is the lowest dose of aspirin with a proven thromboprophylactic effect. Key results: The median percentage inhibition of thromboxane B2 levels by 30 mg or 80 mg aspirin was 90.3% (range 83.1–96.0%) and 98.0% (range 96.8–99.2%) respectively. The inhibition by concurrent administration of slow release diclofenac and 80 mg aspirin was 98.1% (range 97.2–98.9%), indicating no interference between aspirin and diclofenac. The inhibition decreased significantly by concurrent administration of immediate release ibuprofen and 80 mg aspirin (86.6%; range 77.6–95.1%) to a level less than 30 mg aspirin. Conclusions and implications: As alternatives are easily available, NSAIDs such as diclofenac should be preferred to ibuprofen for combined use with aspirin.

Aims To compare the effects of nabumetone and meloxicam, two cyclo-oxygenase-2 (COX-2) preferential nonsteroidal anti-inflammatory drugs (NSAIDs), on platelet COX-1 activity and platelet function. Methods Twelve healthy volunteers (3 male, 9 female, median age 22 years) participated in an open, randomized, cross-over trial of nabumetone 1000 mg twice daily vs meloxicam 7.5 mg twice daily during 1 week with 2 weeks wash-out. After a second 2 week wash-out period, one dose of indomethacin 50 mg was given as a positive control to check for NSAID induced inhibition of platelet function. COX-1 inhibition was measured as percentage inhibition of serum TXB2 generation in clotting whole blood, and as closure time with use of the platelet function analyser PFA-100. Data are reported as median with range. Paired variables were analysed using Wilcoxons signed rank test. Results TXB2 levels decreased significantly after all three medications, but percentage inhibition after nabumetone and indomethacin (88% and 97%, respectively) was significantly higher than after meloxicam (63%) (P

In 2013 the European Medicines Agency declared that diclofenac is contraindicated in patients with arterial thrombotic complications, based on a meta-analysis of randomised controlled trials on the adverse reactions of NSAIDs. The same decision was taken for coxibs some years earlier. The Dutch authorities (CBG/MEB) informed physicians and pharmacists about this decision without taking into account whether these patients were using prophylactic acetylsalicylic acid or not. It has been shown that NSAIDs with high COX-1 affinity like ibuprofen and naproxen cause a pharmacodynamic interaction with the inhibition of thromboxane synthesis by acetylsalicylic acid. This interaction does not occur with relatively COX-2-selective NSAIDs such as coxibs and diclofenac. Therefore, in patients who use acetylsalicylic acid for thromboprophylaxis, contraindicating coxibs or diclofenac is not justified, on the contrary: they are preferable.

Ciprofloxacin in low doses is, in volunteers, effective for decontaminating the digestive tract [elimination of aerobic Gram-negative bacilli (GNB)] without disturbing colonization resistance. Before using this concept in neutropenic patients, we investigated if a low dose quinolone is still effective when the colonization resistance is disturbed by another antimicrobial agent. Ciprofloxacin 20 mg daily was effective in eliminating Gram-negative bacilli from the digestive tract in 4/5 volunteers, in 1 volunteer the GNB persisted in low concentration. No colonization with exogenous resistant GNB occurred. Following impairment of colonization resistance by addition of clindamycin 300 mg daily, 3/5 volunteers became colonized by spontaneously acquired exogenous GNB resistant to ciprofloxacin. We conclude that selective decontamination with a quinolone in low dosage cannot be recommended in neutropenic patients because there is, in the case of disturbed colonization resistance, a real risk of acquisition of quinolone-resistant strains.

The influence of co-trimoxazole on colonization resistance of the bowel was investigated in six healthy volunteers, by measuring the numbers of indigenous aerobic flora and of a co-trimoxazole resistant challenge strain of Klebsiella pneumoniae. Impairment of colonization resistance of the bowel was shown by a significant increase in the numbers of yeasts in the faeces of five of six volunteers, by a significant increase in the numbers of Gram-negative bacilli in the faeces of two of six volunteers, and by facilitation of colonization of the bowel by the challenge strain in all volunteers. Impairment of colonization resistance of the mouth was shown by the development of glossitis caused by Candida albicans in two volunteers, and by a significant increase in the numbers of yeasts in mouth washings from four volunteers. It is concluded that co-trimoxazole impairs colonization resistance of the gastro-intestinal tract.

The objective of this study was to assess the effect of a novel regimen of antibiotic prophylaxis on the incidence of lower respiratory tract infection in patients requiring prolonged (at least five days) mechanical ventilation. The design was a controlled, prospective, randomized trial, with blinded comparison of the groups regarding the incidence of respiratory tract infection in an intensive care unit of a university hospital. After determination of the APACHE II score for severity of disease, 88 patients were randomly divided in three groups. Twenty-four of these patients did not complete five days of mechanical ventilation, and eight were withdrawn for other reasons. Fifty-six patients (18 in group 1, 21 in group 2, 17 in group 3) completed the study. Patients in both control groups 1 and 2 did not receive antibiotic prophylaxis, but the two groups differed in the antibiotic policy in case of infection. Patients in group 3 received antibiotic prophylaxis consisting of norfloxacin, polymyxin E, and amphotericin B, applied topically in oropharynx and stomach from time of ICU admission until extubation, and intravenous cefotaxime 500 mg three times a day during the first five days of admission. In both control groups, about 90 percent of the patients acquired microbial colonization of oropharynx or stomach. In group 3, only 12 percent and 24 percent of the patients acquired colonization of oropharynx and stomach, respectively (p

A novel regimen of selective decontamination (SDD) with initial systemic cefotaxime prevented bacterial colonization of the oropharynx and stomach in mechanically ventilated patients. In a three-group study of all patients receiving prolonged mechanical ventilation, patients in control groups A and B received antibiotics only when infection was present. In group A, antibiotics that disturb colonization resistance (CR) were used. In group B, antibiotics use was restricted to antibiotics not affecting CR. Patients in group C received SDD, consisting of norfloxacin, polymyxin E and amphotericin B, administered via a gastric tube and applied to the oropharynx. Group C patients further received an initial five day course of cefotaxime, 500 mg tid. The lower respiratory tract was colonized with microorganisms on admission in about half of the patients, and this persisted in both control groups. In group C, lower respiratory tract colonization was eliminated in all patients after five days. In both control groups about 90% of the patients acquired microbial colonization of the oropharynx and stomach, mostly with Gram-negative bacilli. In group C, only 12% and 24% of the patients acquired colonization of the oropharynx and stomach respectively (P less than 0.001). The oropharynx and stomach were the major sources of microorganisms causing lower respiratory tract infection in both control groups. In group C, elimination of oropharyngeal and gastric colonization completely prevented lower respiratory tract infection from these sources.

The PFA-100 device is increasingly used for assessing platelet function. Its use to monitor anti-platelet therapy, like acetylsalicylic acid (ASA), has been described. In most studies single PFA-100 measurements were used. In this study, we evaluate the influence of ASA on duplicate measurements using collagen/epinephrine cartridges. Twelve healthy volunteers received a single dose of 160 mg ASA and 12 other healthy volunteers received 30 mg ASA during 10 days followed by 80 mg ASA during 10 days. PFA-100 measurements were performed in duplicate 1 and 24 h after the final intake of medication. The mean coefficient of variation of duplicate measurements before medication was 8.4% and at least two times higher after the intake of a single dose of 160 mg ASA or 30 mg ASA during 10 days. Per individual, huge differences between duplicate measurements were observed after ASA ingestion. Differences were less pronounced after ingestion of 80 mg ASA during 10 days, because six of 12 volunteers had a maximum PFA-100 value > 300 s in both measurements. As a consequence, one should be cautious to use the PFA-100 to monitor ASA therapy in individual patients.

Pefloxacin (400 mg twice daily) was administered orally for infection prophylaxis in neutropenic patients. Diffusible fecal pefloxacin concentration was determined by bioassay during 24 neutropenic periods. The median diffusible fecal pefloxacin concentration was 187 micrograms/g. This concentration was comparable with those found in volunteers following oral and intravenous administration of pefloxacin (400 mg twice daily) (median of 171 and 155 micrograms/g, respectively). From this study, it is concluded that pefloxacin administered orally results in a predictable high diffusible fecal concentration which leads to effective elimination of susceptible aerobic gram-negative bacilli from the colonic flora.

Sir, Sevelamer hydrochloride (Renagel) is a calcium-free nonabsorbable phosphate-binding cationic polymer marketed for the treatment of hyperphosphataemia in patients undergoing renal function replacement [1]. Furosemide is a loop diuretic. Large doses of furosemide have been employed as an adjunct to other therapies in patients with acute and chronic renal failure. In some patients, the use of furosemide may permit a slightly more liberal fluid intake. This is very important for the quality of life of these patients. A 64-year-old female on haemodialysis thrice weekly started with sevelamer for hyperphosphataemia. Her urine production was 950 ml/day with furosemide 250 mg twice daily. Upon starting sevelamer, 800 mg with breakfast, 800 mg at lunchtime and 1600 mg with dinner, she noticed that her urine production stopped within 24 h after taking the first sevelamer capsule. After sevelamer withdrawal, her urine production increased within 24 h to her previous level. Her urine production stopped again within 24 h after resumption of sevelamer and increased after withdrawal. Unfortunately, we do not know if the patient gained weight or if there were any blood pressure fluctuations during the time the urine production stopped. At present the patient takes furosemide 500 mg once daily in the morning and sevelamer twice daily 1600 mg at lunch and dinner. Her urine production is stable as before.

Cephradine has been described as one of the antimicrobials that do not impair microbial colonisation resistance. However, this view was based on data obtained in animals, and has not been proven in man. In this study we investigated the influence of cephradine, 500 mg twice daily, on microbial colonisation resistance in six healthy volunteers. Increase in the faecal concentrakion of gram-negative bacilli, aerobic gram-positive cocci or yeasts, and increase in secondary colonisation by strains acquired spontaneously or administered deliberately (challenge), were used as indicators for disturbance of the flora that provides colonisation resistance. In two of six volunteers none of these indicators was found to be positive. In the other four volunteers one or more indicators became positive. It is concluded that even this low dosage of cephradine may impair colonisation resistance. Therefore the view that cephradine does not impair colonisation resistance in a dosage of up to 9 g daily is probably incorrect. Keywords: Colonisation resistance; Cephradine; Indigenous aerobic flora.

In a double-blind, placebo-controlled study in 125 patients undergoing a cholecystectomy, a comparison was made of the quality of post-operative pain relief during ‘patient-controlled’ intake of sublingual buprenorphine in combination with either rectally administered naproxen 1000 mg/24 h, paracetamol 4000 mg/24 h or a placebo. Results obtained in 97 patients were analysed. Five of these patients needed a rescue medication with morphine hydrochloride intramuscularly because of insufficient pain relief or because of nausea and vomiting. The quality of pain relief, as measured on a four-point scale, was comparable in all three groups throughout the study period and no significant differences became apparent. Only on the day of surgery (day 0) was intake of buprenorphine significantly greater in the placebo group (2.3 tablets/24 h) than in the naproxen and paracetamol groups (1.8 and 1.5 tablets/24 h, respectively). It is concluded that after cholecystectomy ‘patient-controlled’ intake of sublingual buprenorphine as a sole agent provides acceptable pain relief in about 80% of patients. More elaborate methods, such as intravenous patient-controlled analgesia, might be necessary to achieve good pain relief in the remainder of these patients.

The influence of pefloxacin, 400 mg twice daily for ten days, on microbial colonization resistance was investigated in six healthy volunteers. In three volunteers impairment of colonization resistance was indicated by a significant increase in the faecal concentration of yeasts. In two of them, impairment of colonization resistance was confirmed by facilitation of colonization by a challenge strain of Klebsiella pneumoniae in the early post-treatment period. It is concluded that pefloxacin impairs colonization resistance in some volunteers. However, during pefloxacin therapy, overgrowth by aerobic bacteria is prevented by the very high antimicrobial concentration in faeces, and after therapy it is prevented by rapid restoration of colonization resistance.

The effects of various types of 3 d antibiotic treatment of mice on the presence of segmented filamentous bacteria (SFBs) in the ileum were measured in order to further characterise these microorganisms. To assess any specific effects of the antimicrobial drugs on SFBs, relative caecal weight, relative number of fusiform-shaped bacteria in the caecum and the number of faecal Enterobacteriaceae were also determined. All drugs tested, i.e. amoxycillin, doxycyclin, gentamicin, vancomycin, ciprofloxacin, trimethoprim, metronidazole, clindamycin, streptomycin and cefotaxim, reduced the presence of SFBs in the ileum, although to different degrees. None of the drugs affected body weight of the mice. There was no correlation of the drug effects on SFBs and those on either relative caecal weight, percentage of caecal fusiforms or faecal Enterobacteriaceae. Thus, the effects of the antimicrobial drugs on SFBs can be considered rather specific. The sensitivity pattern of SFBs suggests that they are facultatively anaerobic bacteria with relatively high sensitivity to antimicrobial drugs. Keywords: Segmented filamentous bacteria; Intestinal bacteria; Small intestine; Mouse; Antibiotics.

The objective of this study was to assess the effect of a novel regimen of antibiotic prophylaxis on the incidence of lower respiratory tract infection in patients requiring prolonged (at least five days) mechanical ventilation. The design was a controlled, prospective, randomized trial, with blinded comparison of the groups regarding the incidence of respiratory tract infection in an intensive care unit of a university hospital. After determination of the APACHE II score for severity of disease, 88 patients were randomly divided in three groups. Twenty-four of these patients did not complete five days of mechanical ventilation, and eight were withdrawn for other reasons. Fifty-six patients (18 in group 1, 21 in group 2, 17 in group 3) completed the study. Patients in both control groups 1 and 2 did not receive antibiotic prophylaxis, but the two groups differed in the antibiotic policy in case of infection. Patients in group 3 received antibiotic prophylaxis consisting of norfloxacin, polymyxin E, and amphotericin B, applied topically in oropharynx and stomach from time of ICU admission until extubation, and intravenous cefotaxime 500 mg three times a day during the first five days of admission. In both control groups, about 90 percent of the patients acquired microbial colonization of oropharynx or stomach. In group 3, only 12 percent and 24 percent of the patients acquired colonization of oropharynx and stomach, respectively (p less than 0.001). This resulted in a reduction of the incidence of lower respiratory tract infection (78 percent in group 1, 62 percent in group 2, 6 percent in group 3 [p = 0.0001]). The regimen of antibiotic prophylaxis studied prevented respiratory tract infection in mechanically ventilated patients. Antibiotic prophylaxis should be considered in all patients expected to require prolonged mechanical ventilation.

The contribution of Escherichia coli to the microbial colonization resistance (CR) of the bowel was investigated in six healthy volunteers. Esch. coli was eliminated from faeces by the administration of a low dose (20 mg daily) of pefloxacin. This did not cause an increase in the faecal concentration of aerobic Gram-positive cocci or yeasts, nor did it facilitate colonization of the bowel by a pefloxacin-resistant challenge strain of Klebsiella pneumoniae. Therefore, Esch. coli does not appear to contribute to the microbial CR. After ten days of pefloxacin, clindamycin 300 mg was administered twice daily for 18 days. Clindamycin caused a significant increase in the faecal concentration of enterococci, yeasts and the K. pneumoniae challenge strain, indicating that the study design was suitable to demonstrate disturbance of microbial CR if it occurred.

The influence of cefotaxime 1000 mg given intravenously bd on microbial colonization resistance was investigated in six healthy volunteers. Administration of cefotaxime allowed colonization of the bowel by a resistant challenge strain of Enterobacter cloacae in all volunteers. The faecal concentration of aerobic flora increased significantly in five of six volunteers. In one the numbers of Gram-negative bacilli, enterococci and yeasts also increased. In the other four the faecal concentration of enterococci and yeasts increased, but Gram-negative bacilli did not rise above pre-treatment level. It is concluded that cefotaxime impairs colonization resistance, although to a variable degree. Therefore the term 'selective decontamination' is not fully justified for prophylactic regimens that include cefotaxime.

The influence of amoxycillin 500 mg tid on microbial colonization resistance was investigated in 11 healthy volunteers. Analysis was performed in each volunteer individually. In the first five volunteers we investigated the influence of amoxycillin on the faecal concentration of Gram-negative bacilli, enterococci and yeasts and on spontaneously occurring secondary colonization. In the next six volunteers we also investigated the influence of amoxycillin on colonization resistance against amoxycillin-resistant challenge strains, in order to be independent of the accidental presence of resistant Gram-negative bacilli. In three volunteers all indicators employed did not show impairment of the anaerobic flora that provide colonization resistance. In five volunteers impairment of this flora was indicated both by increase of the faecal concentration of aerobic flora and by increase of spontaneously occurring secondary colonization or facilitation of colonization by the challenge strains. However, in the other three volunteers there was no concordance between the investigated indicators of the influence of amoxycillin on colonization resistance. Possible explanations are discussed. It is concluded that increase of the faecal concentration of aerobic flora is a more reliable indicator of impairment of the anaerobic flora that provides colonization resistance than increase of secondary colonization by strains acquired spontaneously or by challenge strains administered deliberately. In one volunteer, who was excluded from the trial, high-level faecal colonization occurred after challenge with Enterobacter cloacae in the pretreatment period.

In 1961 toondeBurke in dierexperimenten aan dat antibiotica een primaire wondinfectie slechts gunstig beInvloeden als zij voor of kort na de bacteriele contaminatie worden toegediend. Het effect is optimaal als reeds tijdens de contaminatie een effectieve weefselconcentratie van het antibioticum bestaat.

The influence of clindamycin, dicloxacillin, minocycline and norfloxacin on the faecal concentration of urobilinogen was investigated. The studied drugs were administered orally in standard dosage for six days to groups of six volunteers. A decrease in faecal concentration of urobilinogen following administration of clindamycin (P less than 0.01) and dicloxacillin (P less than 0.05) was found. The possible predictive value of a decrease of the faecal level of urobilinogen as an indicator for the impairment of microbial colonization resistance and for the risk of failure of oral anticonceptive treatment is discussed. It is suggested that clindamycin and dicloxacillin should not be combined with oral anticonceptive treatment unless more specific investigations have excluded interaction of these drugs with the oestrogen metabolism in the bowel.

We investigated the influence of oral administration of amoxycillin, erythromycin and roxithromycin on colonization resistance in healthy volunteers. Antibiotics were administered in a randomized cross-over design. No effect on the colonization resistance of the oropharynx could be demonstrated. Amoxycillin decreased the colonization resistance of the bowel against Enterobacteriaceae and yeasts, whose median concentration in faeces increased 100-fold and 30-fold respectively. Roxithromycin and erythromycin decreased the concentration of Enterobacteriaceae in faeces. Secondary colonization with Enterobacteriaceae was detected as often following roxithromycin as following amoxycillin, but the level of colonization with these bacteria was much higher following amoxycillin. Following roxithromycin and erythromycin the level of secondary colonization did not exceed the original concentration of Enterobacteriaceae, showing that these antibiotics did not decrease the colonization resistance against Enterobacteriaceae. The appearance of secondary colonization in faeces at levels equal to or lower than the concentration of Enterobacteriaceae before administration of antibiotics, should not be regarded as proof of disturbance of colonization resistance.

The influence of oral administration of cefaclor, phenethicillin, co-trimoxazole and doxycycline on colonization resistance (CR) of the oropharynx and colon in healthy volunteers was studied. Antimicrobial agents were administered in a randomized cross-over design. No effect on CR of the oropharynx could be demonstrated. Phenethicillin decreased CR of the colon against Enterobacteriaceae (P = 0.001). Co-trimoxazole significantly decreased the concentration of Enterobacteriaceae in faeces (P = 0.03) but the decrease caused by cefaclor and doxycycline did not reach statistical significance. Administration of antimicrobial agents increased the appearance of secondary colonization by Enterobacteriaceae in faeces, especially when Escherichia coli was eliminated. During administration of phenethicillin, secondary colonization occurred at a concentration exceeding 10(7)/g in some volunteers. Following administration of cefaclor, co-trimoxazole and doxycycline, elimination of E. coli may result in the substitution by resistant Gram-negative bacilli in low concentrations.

The autochthonous anaerobic bacterial flora in the mucosal layer of the gastrointestinal tract limits colonization by aerobic potential pathogens. This effect is called colonization resistance. Colonization of the digestive tract by potentially pathogenic microorganisms precedes infection in patients with leukopenia and in cases of mechanical ventilation and can be prevented by long-term administration of antimicrobial agents that spare the autochthonous anaerobic bacterial flora of the mucous membranes, a concept known as selective decontamination. Antimicrobial agents active against anaerobic flora reduce colonization resistance, permitting colonization by and overgrowth of potentially pathogenic microorganisms and possibly leading to infections with resistant microorganisms. A distinction can be made between antimicrobial agents that reduce colonization resistance and those that leave it intact by examining the effect of antimicrobial agents on aerobic intestinal flora of mice and humans.

Oral norfloxacin prevented Gram-negative bacilluria in female patients with hip fractures, who needed medium-term transurethral catheterization. This was shown in a placebo-controlled double-blind study of 34 patients. Seventeen of these received a suspension containing 200 mg norfloxacin and 500 mg amphotericin B, twice daily. In the placebo group, six cases of Gram-negative bacilluria had occurred by day 7, as compared with no cases during a median time of catheterization of 23 days in the group on medication. Bacteriuria, either by Gram-positive cocci or by Gram-negative bacilli, was observed in 50% of patients on placebo by day 7; in the treatment group this was the case by day 17 (P less than 0.001). Subsequent bacteriuria with Gram-positive cocci was eliminated by nitrofurantoin (50 mg qid) within four days. Norfloxacin is very suitable for the prevention of Gram-negative bacilluria, because it decontaminates Gram-negative bacilli from the bowel, reaches high concentrations in urine and rarely produces resistant variants.

All neuroleptics have a cerebral dopamine receptor blocking effect. This is the best documented explanation for their anti-psychotic effect. Furthermore, they act to a widely differing extent in a blocking manner to other central neurotransmitters, such as noradrenaline, acetylcholine, histamine, and serotonin. During the last couple of years quantitative data have been produced, enabling a more rational choice of neuroleptics. Based on these data and a number of pharmacokinetic considerations, a provisional scheme has been elaborated for the choice of neuroleptics in some clinical situations in psychogeriatrics. Our own experiences with this scheme are promising. It allowed us to restrict the use of neuroleptics to five drugs. The neuroleptics with a strong sedative and anticholinergic action, such as alimemazine, promazine and levomepromazine, being potentially dangerous to particularly elderly patients, are no longer used.

A prospective randomized study was performed to evaluate the effectiveness of selective decontamination (SDD) in combination with short-term systemic antimicrobial prophylaxis in patients requiring prolonged (at least five days) mechanical ventilation. After stratification by means of the APACHE II score, patients were randomly allocated to one of three groups. Patients in both control groups I (n = 18) and H (n = 21) did not receive antibiotic prophylaxis. However, in cases of infection, patients in group I received antibiotics which may affect indigenous flora, whereas those in group H received only antibiotics with no influence on colonization resistance. Patients in group III (n = 17) received SDD from admission until extubation. Our SDD regimen consisted of norfloxacin 50 mg, polymyxin E 200 mg and amphotericin B 500 mg q.i.d. via the gastric tube; a sticky paste containing 2% of the same antibiotics was applied to the oropharynx q.i.d. Group III patients further received intravenous antibiotic prophylaxis (cefotaxime 500 mg t.i.d.), during the first 5 days of admission. In both control groups about 90% of the patients acquired microbial colonization of oropharynx or stomach, lower respiratory tract infection occurred in 14 patients (78%) in group I and in 13 patients (62%) in group II. Microorganisms causing lower respiratory tract infection were mostly gram-negative bacilli originating from the oropharynx or stomach. In group III patients microbial colonization of the oropharynx and stomach was significantly reduced, and only one patient (6%) acquired lower respiratory tract infection, a highly significant reduction (p = 0.001).