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We report a case of infective iliopsoas bursitis, and to our knowledge a similar case has not been described. The anatomical relation between the bursa and the hip, and related pathological conditions are reviewed. The contribution of CT-guided catheterisation is emphasised as it allows aspiration of fluid, injection of radio-opaque material and lavage.
The clinico-pathological entity of flucloxacillin-associated cholestatic hepatitis is described and the recognition and documentation of cholestasis associated with flucloxacillin and with related isoxazolyl-penicillins (cloxacillin, dicloxacillin) is examined on an international basis, with particular reference to Australia. Data were obtained from the literature, from the Australian adverse drug reaction monitoring agency and from the Collaborative Centre for International Drug Monitoring (World Health Organisation) in Sweden. Approximately 600 cases of flucloxacillin-associated cholestatic hepatitis were collected, as well as 164 cases associated with other isoxazolyl penicillins. Jaundice and pruritus may first appear several weeks after administration of the drug has ceased and typically are severe and protracted. Liver tests may be abnormal for months after symptomatic recovery. Death is uncommon. Liver pathology shows centrizonal bile stasis with portal tract inflammation and variable loss of bile ducts. Approximately 1 in 15,000 users of flucloxacillin will develop the reaction. Increasing age (> 55 years) and prolonged intake (> 14 days) are particular risk factors. Cholestasis associated with cloxacillin/dicloxacillin appears to be similar in nature but is less well defined. Recognition and reporting of the reaction have been uncommon in the United Kingdom inter alia and high in Sweden and Australia, although estimates of risk have been similar. In Australia, the remarkably high rate of reports appears to be the result of sustained publicity for the reaction. There is only a trickle of reports of cholestatic hepatitis in association with the use of cloxacillin and dicloxacillin from the USA and Canada. The high level of awareness of the reaction and consequential regulatory action so far have not resulted in a diminution of its occurrence in Australia.
Antibiotic prophylaxis with 2 g flucloxacillin was given 2 h before operation in 23 adult patients undergoing knee replacement operations for rheumatoid arthritis or osteoarthrosis. The mean extracted concentration of flucloxacillin obtained at operation was 12.9 micrograms/ml (SD 5.25) in synovial fluid; 2.9 micrograms/g (SD 3.59) in synovium; 2.0 micrograms/g (SD 1.48) in cancellous bone and 1.3 micrograms/g (SD 1.25) in cortical bone. The minimum inhibiting concentration (MIC) value for flucloxacillin was usually 0.25 micrograms/g against Staphylococcus aureus. Therapeutically active concentrations were thus obtained. There were no adverse reactions from the antibiotic administration.
The fate of flucloxacillin and its active metabolite hydroxyflucloxacillin was studied in a group of patients with impaired kidney function. Flucloxacillin was administered orally or intravenously. Peak levels of hydroxyflucloxacillin were obtained between 150 and 250 min after the administration of flucloxacillin. The plasma concentrations obtained after a therapeutic dose of flucloxacillin were well above the concentration (i.e. 1-2 microgram/ml) generally considered to be the effective minimum for isoxalyl penicillins. The plasma half life of the metabolite was twice as long as that of flucloxacillin (295 min and 154 min, respectively). The nonprotein-bound fraction of hydroxyflucloxacillin in plasma from patients was twice as large as that of its parent compound (16.2 vs. 8.1%). This was also observed in normal human plasma, although protein binding in the latter was higher than in uraemic plasma. Some accumulation of hydroxyflucloxacillin may occur during flucloxacillin therapy with dosage intervals of 6 h.
Flucloxacillin 50 mg/kg b.w. was administered intravenously (in combination with ampicillin/gentamicin) and orally (with amoxicillin) to 9 newborn infants (gestational age 33-41 weeks) to treat bacterial infections. The concentrations of flucloxacillin in plasma and urine after i.v. injection were analysed according to an open two-compartment model, and the plasma protein binding of flucloxacillin and its distribution to blood cells and plasma water in whole blood were determined. Considerable differences were found from values reported in adults. The terminal half-life averaged 4 h 38 min and was significantly correlated with gestational age. Plasma clearance was low (0.744 ml X min-1 X kg-1), due to the small renal clearance (0.182 ml X min-1 X kg-1), whilst non-renal clearance (0.563 ml X min-1 X kg-1) was approximately the same as in adults. The mean apparent volume of distribution of total drug (Vz) was 0.280 l/kg. The corresponding volume of distribution of unbound drug (Vu1 + Vu2) was 1.74 l/kg, which indicates considerable extravascular drug binding. The plasma protein binding of flucloxacillin (mean 86.3%) was significantly correlated with gestational age and the bilirubin/albumin concentration ratio. Bioavailability after oral administration, when corrected for changes in terminal half-life, was 47.7%, which is only slightly lower than that reported in adults. Since the plasma concentrations after both i.v. and oral administration were well above the MIC-values generally reported for Staphylococcus aureus, and since few side-effects were observed, intravenous injection or, in selected cases, orl administration of flucloxacillin appears to be a reliable therapy for the treatment of infections due to sensitive strains of S. aureus in premature newborn infants.
The pharmacokinetics of flucloxacillin in plasma and tissue fluid after i.v. infusion of 1 g was analyzed according to an open two-compartment model in 19 patients with bradyarrhythmias (mean age 70.8 years) admitted for implantation or replacement of a permanent pacemaker system. After the first infusion of flucloxacillin (5 min), the distribution phase was rapid (t 1/2 alpha = 0.13 h). The plasma half-life of elimination (t 1/2 beta) was 1.51 h, which is almost twice as long as reported in healthy volunteers. Total plasma clearance (93.1 ml/min) was also lower than is usually found in healthy individuals, due to low renal clearance of flucloxacillin (60.2 ml/min). The total apparent volume of distribution during the beta-phase (Vdarea) was 0.172 l/kg and distribution in the central compartment (Vc) 0.064 1/kg. In each patient plasma protein binding and drug distribution to plasma water, proteins and blood cells in whole blood were determined. Binding in plasma to proteins was 91.0% and distribution to blood cells in whole blood 13.8%. The mean distribution volume of free flucloxacillin during the beta-phase (Vd beta free) was 2.18 1/kg, which exceeds total body water, suggesting possible intracellular distribution and substantial tissue binding. Plasma concentrations of flucloxacillin after the fourth dose (1 g t.i.d.) were very similar to those obtained after the first infusion and those predicted from the single dose kinetics. The concentration of flucloxacillin in fluid from the pacemaker pockets in 5 patients averaged 12.1 micrograms/ml and 9.5 micrograms/ml at 1 and 5 h, respectively, which was more than ten times the MIC-values for Staphylococcus aureus and S. epidermidis.(ABSTRACT TRUNCATED AT 250 WORDS)
The distribution of cloxacillin and flucloxacillin in whole blood from seven newborn infants and their mothers was determined in vitro by equilibrium dialysis at 37 degrees C. Seven healthy, non-pregnant women of reproductive age served as controls. The distribution of the penicillins to erythrocytes was the same in the infants as in the adults. It was significantly lower in the presence of plasma albumin than when plasma was replaced by isotonic phosphate buffer. The plasma protein binding of cloxacillin and flucloxacillin in 22 infants was significantly lower than in the controls, but was slightly higher than in the mothers. A significant correlation between binding of cloxacillin and flucloxacillin in the same individual suggested that the two drugs were bound to similar sites. During the first postnatal week binding in infant plasma decreased. This change was correlated with an increase in the bilirubin levels. In the mothers, the binding increased during the first week after delivery. On the basis of the distribution data, maternal to fetal plasma and whole blood concentration ratios at equilibrium were calculated. These ratios were lower for flucloxacillin (medians 0.770 and 0.821, respectively) than for cloxacillin 0.996 and 1.094). Accordingly, at equilibrium somewhat higher levels of flucloxacillin should appear on the fetal than on the maternal side, whereas the concentrations of cloxacillin would be expected to be approximately the same.
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Two-hundred and fifty-two patients were included in a prospective, randomized, double-blind trial comparing the efficacy of flucloxacillin with that of cefazolin for clean orthopedic surgery. The preventive antibiotic regimen consisted of three 1-g injections perioperatively. There were 126 patients in each group, and the follow-up period was at least 6 months. Two deep (1.6%) and five superficial (4.0%) infections occurred in the flucloxacillin group. Three deep (2.4%) and five superficial (4.0%) infections developed in the cefazolin group.
The releasing kinetic of antibiotics from tricalcium phosphate beads was studied in animal experiments. The porous TCP-beads were filled with antibiotics and coated with biodegradable substances for delaying the release of the antibiotics. There were high tissue levels of antibiotics in the surrounding bone for many days. This method gains an increase in therapeutic safety in treatment of osteomyelitis. The coated TCP-antibiotic beads are used simultaneously as bone graft and for treatment of the bone infection. There is no need for further operation.
The combination of amoxicillin and flucloxacillin not only widens the spectrum of pathogenic organisms covered by either of the substances alone; synergy has also been observed, particularly against beta-lactamase-producing organisms. For this reason, the possible interaction of these two penicillins regarding their pharmacokinetics was investigated with respect to therapeutic application. The parameters were calculated on the basis of an open two-compartment model. The highest serum levels of amoxicillin from 551 to 1074 mg/l when 4 g were administered alone, and from 403 to 1133 mg/l when administered together with 1 g flucloxacillin. Flucloxacillin concentrations ranged from 118 to 357 mg/l when administered alone, and from 151 to 226 mg/l in the presence of amoxicillin. Thus, there is no significant difference in the peak levels of either substance when given alone or in combination. The pharmacokinetic parameters of both substances basically do not depend on the presence of the other. A slight decrease was observed in the distribution rate of amoxicillin from the central to the peripheral compartment in the presence of flucloxacillin. Its relevance is questionable, however, since the effect was only minor.
In a randomized study, 42 patients undergoing extensive maxillo-facial surgery (correction of the position of the mandible or maxilla by using autologous bone transplants) received prophylactically ten-day courses of either flucloxacillin or amoxicillin with clavulanic acid. Patients were comparable with regard to age and type of surgery. During the prophylactic treatment the effect of antibiotics used on the microbial flora of the alimentary tract was studied. Patients receiving flucloxacillin showed increased numbers of Klebsiella spp. isolated from the faeces (59% of the patients versus 19% of the patients receiving amoxicillin with clavulanic acid). Patients receiving amoxicillin with clavulanic acid showed higher colonization rates of oropharynx with Enterobacteriaceae than patients receiving flucloxacillin (ten patients versus five patients). 60% of those strains isolated from patients receiving amoxicillin with clavulanic acid were resistant to this combination, as compared to 20% of gram-negative bacilli isolated from patients receiving flucloxacillin. In 50% of patients receiving amoxicillin with clavulanic acid, colonization of the gut with yeast occurred, as compared to 18% of patients receiving flucloxacillin. Only one infection leading to a partial loss of the graft was seen in the group of patients receiving flucloxacillin.
Two strains each of sensitive, penicillinase-producing, methicillin-resistant and "tolerant" Staphylococcus aureus were used to infect mice intramuscularly. The mice were then treated with three doses each of fosfomycin, vancomycin, rifampicin, fusidic acid, penicillin G, flucloxacillin or cefazolin intravenously. Infections due to sensitive strains were effectively treated with all antibiotics investigated except fusidic acid. Fosfomycin, vancomycin, rifampicin and flucloxacillin showed the best activity against penicillinase-producing strains. Fosfomycin and vancomycin were equally effective against infections due to methicillin-resistant S. aureus. Infections caused by "tolerant" strains again responded best to fosfomycin, vancomycin and rifampicin.
Toxic shock syndrome (TSS) is a well-defined clinical syndrome attributed to certain exotoxins produced by Staphylococcus aureus. The acute episode is often characterized by a toxic encephalopathy, possibly caused by direct neurotoxicity of these exotoxins, although this mechanism has never been proven. We describe a patient who developed TSS, meningitis and cauda equina syndrome simultaneously several days after lumbar laminectomy. A space-occupying lesion was excluded. Enterotoxin C-producing S. aureus was cultured from the surgical wound and the cerebrospinal fluid (CSF). The patient recovered from TSS but remained partially paralyzed. Presumably the cauda equina syndrome was caused by neurotoxic effects of the intrathecally produced S. aureus exotoxins. This case provides evidence for the neurotoxic effects of TSS-associated S. aureus exotoxins.
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The pharmacokinetics of dicloxacillin and flucloxacillin were studied in 12 healthy volunteers after oral administration. The participants received a single dose of either dicloxacillin (0.5 g, 0.75 g or 1.0 g) or flucloxacillin (0.75 g) in a cross-over fashion. Antibiotic concentrations were determined in serum and urine by bioassay and followed for 8 and 24 h, respectively. The three dicloxacillin dosages showed no significant differences for the serum elimination half-lives (t1/2 beta, median: 72 min). Comparing 0.75 g flucloxacillin with the same dose of dicloxacillin, no significant differences between the values of Cmax, t1/2 beta and AUC were found. Protein binding as determined by ultrafiltration in pooled serum was 94.7-96.2% for flucloxacillin and 96.4-97.2% for dicloxacillin. The serum bactericidal titers were similar for the two drugs. In conclusion, dicloxacillin and flucloxacillin showed similar pharmacokinetic behavior after 0.75 g doses in human volunteers.
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