[Effects of floxacillin on the liver. 3 cases of floxacillin-induced cholestatic liver disease].
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A severe and prolonged form of biopsy-proved cholestatic hepatitis occurred in a 45-year-old man who had received floxacillin for two weeks preceding the episode of drug-related cholestatic injury. Immunologic tests revealed evidence of in vitro sensitization to the drug as well as to the serum of a normal subject collected after ingestion of floxacillin. Floxacillin should be added to the list of drugs causing cholestatic hepatitis, most likely by an immunologic mechanism.
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Methods are described for the preparation of pure crystalline samples of the penicilloic and penilloic acids of penicillin G, carbenicillin, cloxacillin, floxacillin, methicillin, penicillin V, and ticarcillin and the penicilloic acids of amoxicillin, ampicillin, phenethicillin, and propicillin. The interaction between the compounds and rabbit antibenzylpenicilloyl antibodies was evaluated by hemagglutination inhibition measurements. A significant correlation was found in this system between the reactivity of penicilloic acids and the corresponding penilloic acids; on average, the penicilloic acids were more reactive on a molar basis by a factor of 11. The results are discussed in terms of the general immunochemistry and side-chain structure of the parent penicillins.
A strategy for empiric antibiotic therapy for orofacial/head and neck bacterial infections that appear as clinical swellings in patients with severe neutropenia is assessed. Daily examinations were made in the hospital. Only those with peripheral blood neutrophil counts < 100/mm3 that persisted for at least 5 days after the commencement of resolution of the swelling were included in this article. The strategy consisted of sequential additions of a beta-lactam/aminoglycoside combination, metronidazole to intensify anaerobe cover and a beta-lactamase stable agent (such as vancomycin and floxacillin) as dictated by clinical signs. Progressive and complete resolution of infection occurred in 26 of 27 patients treated.
A 53-year-old granulocytopenic woman with malignant lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy, including doxorubicin (Adriamycin) and autologues bone marrow transplantation, presented in the clinical state of "refractory septic shock" caused by Escherichia coli. Despite inotropic treatment with dopamine, dobutamine, and norepinephrine infusion, the patient's condition did not improve, but during treatment with amrinone and angiotensin II infusion, the septic shock was reversed. The patient was monitored with a pulmonary artery catheter and underwent repeated echocardiographic examinations. Antibiotic treatment with thienamycin and floxacillin was given. The initial reduction in cardiac performance in this patient may be explained by a state of true down-regulation of the myocardial beta-receptors. Apparently these beta-receptors were bypassed via the enzymatic action of amrinone upon cyclic monoadenosine phosphate. This is, to our knowledge, the first doxorubicin-treated patient with septic shock refractory to conventional vasopressor therapy whose condition reversed by inotropic treatment with amrinone and angiotensin II. This treatment may prove to be an alternative choice for patients developing "refractory septic shock" unresponsive to treatment with norepinephrine, dobutamine, and dopamine.
The activities of a range of antibiotics on Staphylococcus aureus organisms that survive within bovine neutrophils in vitro were studied in mice. Cloxacillin, floxacillin, and cephradine failed to kill intracellular staphylococci but increased the organisms' sensitivity to killing by lysostaphin after neutrophil disruption. Fusidate and clindamycin caused an apparent small reduction in viable intraleukocytic S aureus, whereas novobiocin did not demonstrate intracellular activity. Substantial intracellular bactericidal effects were shown in vitro by rifampin and rifamycin SV, even at concentrations in slight excess of the minimum inhibitory concentration. In a mouse model of chronic mastitis, intramammary therapy with rifampin was more effective in reducing viable S aureus in infected glands than was therapy with rifamycin SV.
CONTEXT: Rifampin-containing regimens are able to cure staphylococcal implant-related infections based on in vitro and in vivo observations. However, this evidence has not been proven by a controlled clinical trial. OBJECTIVE: To evaluate the clinical efficacy of a rifampin combination in staphylococcal infections associated with stable orthopedic devices. DESIGN: A randomized, placebo-controlled, double-blind trial conducted from 1992 through 1997. SETTING: Two infectious disease services in tertiary care centers in collaboration with 5 orthopedic surgeons in Switzerland. PATIENTS: A total of 33 patients with culture-proven staphylococcal infection associated with stable orthopedic implants and with a short duration of symptoms of infection (exclusion limit <1 year; actual experience 0-21 days). INTERVENTION: Initial debridement and 2-week intravenous course of flucloxacillin or vancomycin with rifampin or placebo, followed by either ciprofloxacin-rifampin or ciprofloxacin-placebo long-term therapy. MAIN OUTCOME MEASURES: Cure was defined as (1) lack of clinical signs and symptoms of infection, (2) C-reactive protein level less than 5 mg/L, and (3) absence of radiological signs of loosening or infection at the final follow-up visit at 24 months. Failure was defined as (1) persisting clinical and/or laboratory signs of infection or (2) persisting or new isolation of the initial microorganism. RESULTS: A total of 18 patients were allocated to ciprofloxacin-rifampin and 15 patients to the ciprofloxacin-placebo combination. Twenty-four patients fully completed the trial with a follow-up of 35 and 33 months. The cure rate was 12 (100%) of 12 in the ciprofloxacin-rifampin group compared with 7 (58%) of 12 in the ciprofloxacin-placebo group (P=.02). Nine of 33 patients dropped out due to adverse events (n=6), noncompliance (n=1), or protocol violation (n=2). Seven of the 9 patients who dropped out were subsequently treated with rifampin combinations, and 5 of them were cured without removal of the device. CONCLUSION: Among patients with stable implants, short duration of infection, and initial debridement, patients able to tolerate long-term (3-6 months) therapy with rifampin-ciprofloxacin experienced cure of the infection without removal of the implant.
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(i) The objective was to determine the range of bone levels of cefuroxime and flucloxacillin achieved after one intravenous (IV) administration of different dosages of cefuroxime and flucloxacillin. (ii) Six groups of five patients participated in the study. The first three groups (A-C) received respectively 1500 mg, 1000 mg, and 500 mg cefuroxime intravenously and the second three groups (D-F) received 2000 mg, 1500 mg, and 1000 mg flucloxacillin intravenously. (iii) Parenteral administration of cefuroxime and flucloxacillin resulted in measurable bone concentrations in all patients. (iv) Large inter-individual variation in bone concentration was observed. (v) The bone concentrations of IV cefuroxime were higher (1500 mg, p = 0.0057; 1000 mg, p = 0.0260) than those of flucloxacillin. The bone concentrations of cefuroxime and flucloxacillin were dose dependent.
The hazards of dealing with infected false femoral aneurysms resulting from intra-arterial narcotic injection are highlighted in six patients. Two patients were human immunodeficiency virus positive and three patients were hepatitis B surface antigen positive. Because of these infections exploration of groin swellings as presumed soft tissue abscesses is potentially hazardous without proper proximal vascular control. All patients underwent reconstruction following arterial ligation and five grafts became infected, with life threatening haemorrhage occurring in four patients. Five grafts have subsequently occluded or have been removed without loss of limb viability, although two patients have been regrafted. A high index of suspicion and assessment by a vascular surgeon, with angiography if indicated, is required in any intravenous drug abuser presenting with a groin swelling following injection. Because of the great risk of graft infection, it is suggested that ligation and debridement alone be carried out, with immediate arterial reconstruction only for non-viability.
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BACKGROUND: The aim of this randomized clinical trial was to determine whether a single intravenous dose of 2 g flucloxacillin could prevent wound infection after primary non-reconstructive breast surgery. METHODS: The study included 618 patients undergoing local excision (n = 490), mastectomy (n = 107) or microdochectomy (n = 21). Patients were randomized to receive either a single dose of flucloxacillin immediately after the induction of anaesthesia or no intervention. Wound morbidity was monitored by an independent research nurse for 42 days after surgery. RESULTS: The incidence of wound infection was similar in the two groups: 10 of 311 (3.2 percent) in the flucloxacillin group and 14 of 307 (4.6 percent) in the control group (chi(2) = 0.75, P = 0.387; relative risk 0.71, 95 percent confidence interval 0.32 to 1.53). The groups also had similar wound scores and rates of moderate or severe cellulitis. Wound infection presented a median of 16 days after surgery. CONCLUSION: The administration of a single dose of flucloxacillin failed to reduce the rate of wound infection after non-reconstructive breast surgery.
The pharmacokinetics and oral bioavailability of flucloxacillin were studied in five female and two male patients (age 68-87 yr) who had been hospitalized for orthopedic surgeries. A single dose of intravenous or oral flucloxacillin sodium (500 mg) was administered in random order on different occasions separated by at least 2 days. Blood and urine samples were taken up to 24 hours after drug administration and levels of flucloxacillin and 5-hydroxymethylflucloxacillin (5-HMF), a major metabolite, were measured by high-performance liquid chromatography. Flucloxacillin elimination, but not oral absorption, was reduced in the elderly, compared with data from young healthy subjects reported elsewhere. Total clearance, renal clearance, and volume of distribution were 0.083 +/- 0.013 L/kg/hr, 0.038 +/- 0.01 L/kg/hr, and 0.184 +/- 0.034 L/kg, respectively. Regression of flucloxacillin renal clearance (Clr) on estimated creatine clearance (CLcr) gave the relationship: Clr = 0.755 (CLcr) + 10.6 (r = 0.91; P = 0.004). Terminal half-lives for flucloxacillin and 5-HMF were 2.21 +/- 0.51 hr and 3.0 +/- 0.75 hr, respectively after intravenous administration. Flucloxacillin was absorbed rapidly after oral administration with a mean absorption time of 0.95 +/- 0.34 hr, and time to reach peak concentration of 1.20 +/- 0.29 hr. The absolute bioavailability of flucloxacillin from capsules was 54.4 +/- 18.8%.
Unlike studies on the antigenicity of penicillins in laboratory animals, limited information is available on the allergenicity of penicillins in man, especially with regard to fine structural allergenic differences between the many different penicillins. Inconsistent with the earlier conclusions of others, our studies suggest that side-chain structures on the penicillin molecule are the major allergenic determinants in many reactions. Immediate allergic reactions to flucloxacillin were observed in a number of patients where diagnosis was confirmed by skin testing and detection of flucloxacillin-reactive IgE antibodies. Quantitative hapten inhibition studies revealed potent inhibition by flucloxacillin and three structurally related penicillins: oxacillin, cloxacillin and dicloxacillin. Analysis of the inhibition results showed that the side-chain group of flucloxacillin, 3-(2-chloro-6-fluorophenyl)-5-methyl-4-isoxazolyl, is recognized by some antibodies and that the 5-methyl-3-phenyl-4-isoxazolyl group, with or without halogen substituents, accounts for the reactivity of other antibodies and for the cross-reactions seen with some other penicillins. Since it is the side-chain group that distinguishes the many different penicillins, and since the side-chain groups are recognized by IgE antibodies in many of the allergic reactions, it is becoming clear that specific assays are required for the detection of IgE antibodies to each of the different penicillins.
Piperacillin was evaluated as an antipseudomonas antibiotic in a double-blind controlled trial involving 18 pulmonary exacerbations of cystic fibrosis. Standard antibiotic treatment (flucloxacillin plus tobramycin) was compared with standard treatment plus intravenous piperacillin administered according to two regimens. No added benefit from piperacillin was demonstrable on the basis of improvement in symptoms, physical signs, weight gain, pulmonary function tests, radiologic signs, or sputum Pseudomonas bacterial counts. Some patients experienced sensitivity reactions to piperacillin. In vitro, piperacillin was a potent antibiotic against all beta-lactamase-producing mucoid strains of Pseudomonas aeruginosa; however, in spite of the fact that adequate serum antibiotic concentrations were achieved, sputum bacterial counts did not correlate with either the clinical status or the use of piperacillin therapy.
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