[Interaction between NSAIDs and acetylsalicylic acid disregarded]. / Interactie NSAID's en acetylsalicylzuur genegeerd.

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.

[Severe vitamin D deficiency and hypocalcaemia after bariatric surgery]. / Ernstige vitamine D-deficiëntie en hypocalciëmie na bariatrische chirurgie.

A 60-year-old man was referred to the accident and emergency department because of muscle cramps and retrosternal pain. Laboratory tests revealed severe vitamin D deficiency and hypocalcaemia. The patient had undergone bariatric surgery several years previously. Disturbances in fat-soluble vitamins and in minerals are a frequent complication after bariatric procedures. Recognition and treatment of these disorders is very important.

The interaction of ibuprofen and diclofenac with aspirin in healthy volunteers.

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 B(2) 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 B(2) 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.

A comparison of the effects of nabumetone vs meloxicam on serum thromboxane B2 and platelet function in healthy volunteers.

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<0.05). Closure times increased significantly after administration of all three medications (P<0.05). Increases in closure time after administration did not differ between nabumetone and meloxicam (24% and 14%, respectively), but were significantly larger after indomethacin administration (63%) (P<0.01). CONCLUSIONS: In the maximum registered dosage, nabumetone inhibits thromboxane production much more than meloxicam, signifying less COX-2 selectivity of the former. However, both nabumetone and meloxicam cause only minor impairment in platelet function in comparison with indomethacin and the difference between them is not significant.

Influence of low dose ciprofloxacin on microbial colonization of the digestive tract in healthy volunteers during normal and during impaired colonization resistance.

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.

Concentration of pefloxacin in feces during infection prophylaxis in neutropenic 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.

Co-trimoxazole impairs colonization resistance in healthy volunteers.

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.

Application of sublingual buprenorphine in combination with naproxen or paracetamol for post-operative pain relief in cholecystectomy patients in a double-blind study.

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.

Influence of pefloxacin on microbial colonization resistance in healthy volunteers.

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.

Antibiotic prophylaxis of respiratory tract infection in mechanically ventilated patients. A prospective, blinded, randomized trial of the effect of a novel regimen.

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.

Decontamination of the bowel by intravenous administration of pefloxacin.

Intravenous administration of pefloxacin 400 mg twice daily rapidly decontaminated the bowel from Gram-negative bacilli in ten healthy volunteers. The faecal concentrations of enterococci and yeasts did not change significantly. Further, pefloxacin did not facilitate colonization of the bowel by a highly resistant challenge strain (Klebsiella pneumoniae, MIC = 56 mg/l). The diffusible faecal concentration of pefloxacin was between 110 and 260 mg/l in all samples from day 3 of treatment onwards. It is concluded that parenteral administration of pefloxacin is very effective for decontamination of the bowel from Gram-negative bacilli and provides reliable prophylaxis against colonization of the bowel by highly resistant Gram-negative bacilli ingested with food.

The contribution of Escherichia coli to microbial colonization resistance.

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.

Prevention of bacterial colonization of the respiratory tract and stomach of mechanically ventilated patients by a novel regimen of selective decontamination in combination with initial systemic cefotaxime.

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.

Influence of cefotaxime on microbial colonization resistance in healthy volunteers.

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.

Influence of amoxycillin on microbial colonization resistance in healthy volunteers. A methodological study.

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.

Effect on colonization resistance: an important criterion in selecting antibiotics.

Infections in humans are most often caused by aerobic microorganisms colonizing the digestive tract. Aerobic microorganisms are constantly entering the digestive tract with food, but colonization is resisted by autochthonous anaerobic flora (microbial colonization resistance) and by host-related factors (physiologic colonization resistance). Antibiotics to which the autochthonous anaerobic flora are sensitive and that achieve sufficiently high concentrations at the sites of colonization will reduce colonization resistance. Consequently, resistant aerobic flora of the digestive tract may reach high concentrations, increasing the risk of superinfection. Therefore, when choosing antimicrobial agents for therapy, the effect on colonization resistance should be taken into account. Immunosuppressed hosts and acutely ill patients undergoing mechanical ventilation can be protected from serious infections by eliminating the most dangerous species of the aerobic endogenous flora, leaving colonization resistance intact. This is called selective decolonization. This article summarizes the effects of antimicrobial agents on colonization resistance.