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The antibiotics dicloxacillin and flucloxacillin induce cytochrome P450-dependent metabolism of warfarin. We explored the influence of these drug–drug interactions on the clinical effectiveness of warfarin therapy due to atrial fibrillation or heart valve replacement. Using the population-based Danish registers, we performed a propensity-score matched cohort study including around 50,000 episodes of dicloxacillin/flucloxacillin matched to phenoxymethylpenicillin and to no antibiotic, respectively. We estimated hazard ratios (HRs) with 95% confidence intervals (CIs) by comparing 21-day (days 7–28) risks of ischemic stroke/systemic embolism (SE) following initiation of each exposure. When compared with phenoxymethylpenicillin, dicloxacillin/flucloxacillin was associated with an HR of ischemic stroke/SE of 2.09 (95% CI 1.51–2.90; strongest for dicloxacillin (HR 2.17; 95% CI 1.56–3.02)). Use of an untreated comparator strengthened the association (HR 2.84; 95% CI 1.97–4.09). Dicloxacillin should be used with caution in patients receiving warfarin. This may also apply to flucloxacillin; however, more data on the risks associated with flucloxacillin exposure during warfarin therapy are needed.

SummaryAim The aim of this study was to study potential cytochrome P450 induction by dicloxacillin. Methods We performed an open-label randomized two-phase 5-drug clinical pharmacokinetic cocktail crossover study in 12 healthy men with and without pretreatment with 1g dicloxacillin three times daily for 10 days. Plasma and urine was collected over 24 hours and the concentration of all five drugs and their primary metabolites was determined using a LC-MS/MS method. Cryopreserved primary human hepatocytes were exposed to dicloxacillin for 48h and changes in gene expression and enzyme activity of CYP3A4, CYP2C9, CYP2B6 and CYP1A2 was investigated. Activation of nuclear receptors by dicloxacillin was assessed using luciferase assays. Results Ten days of treatment with dicloxacillin resulted in a clinically and statistically significant reduction in the area under the plasma concentration-time curve from 0-24h of omeprazole (CYP2C19) (geometric mean ratio (GMR) [95% confidence interval (CI)]: 0.33 [0.24-0.45]), tolbutamide (CYP2C9) (GMR [95% CI]: 0.73 [0.65-0.81]) and midazolam (CYP3A4) (GMR [95% CI]: 0.54 [0.41-0.72]). Additionally, other relevant pharmacokinetic parameters were affected indicating induction of CYP2C and CYP3A4-mediated metabolism by dicloxacillin. Investigations in primary hepatocytes showed statistically significant dose-dependent increase in P450 expression and activity by dicloxacillin, caused by activation of pregnane X receptor. Conclusions Dicloxacillin is an inducer of CYP2C- and CYP3A-mediated drug metabolism and we recommend caution when prescribing dicloxacillin to users of drugs with a narrow therapeutic window.

SummaryAim The most common pathogen in Denmark, to cause postoperative infections, is Staphylococcus (S.) aureus (1). Despite using prophylactic antibiotics, infections are still seen. Whether the tissue concentration is above the minimal inhibitory concentration (MIC) for the pathogen is unknown. Thus, the concentration of dicloxacillin in muscle and adipose tissue was measured after intravenous administration, in healthy men. Methods MIC for dicloxacillin against S. aureus was determined using the broth macrodilution method. A microdialysis (MD) catheter was placed in the subcutaneous tissue of the abdomen and in the lateral vastus muscle of the thigh of six healthy male volunteers. They were given 2 g dicloxacillin intravenously. Samples from blood and MD fluid were collected. The unbound dicloxacillin was isolated from plasma. Samples were analyzed with High Performance Liquid Chromatography. Results The maximum concentration was reached in muscle tissue after 0.5 hours and in adipose tissue after 0.8 hours. AUC0-6h for the dicloxacillin concentration in adipose tissue was significantly lower when compared to the unbound dicloxacillin concentration in plasma. The dicloxacillin concentration was above the MIC for sensitive S. aureus for a minimum of 2.3 and a median of 4.1 hours in muscle tissue and a minimum of 1.8 and a median of 3.2 hours in adipose tissue. Conclusions The unbound dicloxacillin concentration in adipose and muscle tissue remained above the MIC for sensitive S. aureus, for a period sufficient for many orthopedic procedures. Whether this is true in patients with compromised circulation this remains to be investigated.

Photoinduced acute exanthematous pustulosis is a rare condition; only few cases of photo‐AEP have been described previously with drugs such as norfloxacin, ciprofloxacin, and enoxacin. In this case, the reaction is seen after intake of dicloxacillin.

The aim of this study was to characterize the antioxidant activity of penicillin G (PG), ampicillin (AMP), oxacillin (OX) and dicloxacillin (DOX) through their reactivity towards reactive oxygen species (superoxide anion radical, O2•; hydroxyl radical, HO• ; peroxyl radical, ROO• ; hydrogen peroxide, H2 O2 ; DPPH• ) using various in vitro antioxidant assays with chemiluminescence (CL) and spectrophotometry as measurement techniques. In hydroxyl radical assays , PG, OX and AMP were found to inhibit the CL signal arising from the Fenton-like reaction in a dose-dependent manner with IC50 = 0.480 ± 0.020 mM, IC50 = 0.569 ± 0.021 mM, and IC50 = 0.630 ± 0.019 mM, respectively. The highest reactivity of PG among the tested penicillins towards the HO radical was confirmed in the deoxyribose degradation assay. In the ABAP-derived ROO radical assay, the radical-scavenging ability of the test penicillins was in the following order: AMP > PG > DOX > OX. The number of reduced DPPH radicals by the drugs tested was

Staphylococcus aureus is often found in orthopaedic infections and may be protected from commonly prescribed antibiotics by forming biofilms or growing intracellularly within osteoblasts. To investigate the effect of non-antibiotic compounds in conjunction with antibiotics to clear intracellular and biofilm forming S. aureus causing osteomyelitis. SAOS-2 osteoblast-like cell lines were infected with S. aureus BB1279. Antibiotics (vancomycin, VAN; and dicloxacillin, DICLOX), bacterial efflux pump inhibitors (piperine, PIP; carbonyl cyanide m-chlorophenyl hydrazone, CCCP), and bone morphogenetic protein (BMP-2) were evaluated individually and in combination to kill intracellular bacteria. We present direct evidence that after gentamicin killed extracellular planktonic bacteria and antibiotics had been stopped, seeding from the infected osteoblasts grew as biofilms. VAN was ineffective in treating the intracellular bacteria even at 10× MIC; however in presence of PIP or CCCP the intracellular S. aureus was significantly reduced. Bacterial efflux pump inhibitors (PIP and CCCP) were effective in enhancing permeability of antibiotics within the osteoblasts and facilitated killing of intracellular S. aureus. Confocal laser scanning microscopy (CLSM) showed increased uptake of propidium iodide within osteoblasts in presence of PIP and CCCP. BMP-2 had no effect on growth of S. aureus either alone or in combination with antibiotics. Combined application of antibiotics and natural agents could help in the treatment of osteoblast infected intracellular bacteria and biofilms associated with osteomyelitis. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1086-1092, 2018.

Fast and accurate analysis is a prerequisite in all analytical fields especially in food, biological, pharmaceutical, and environmental samples. The new trend of ultra performance liquid chromatography (LC) has the main drawback of expensive instrumentation, which can't be easily found in low-budget analytical laboratories. The evolution of core shell technology has contributed to this direction, since ultra high efficiency can be achieved on common LC instrument platforms. Herein the novel core shell analytical column, KINETEX ™2.6 µm, (150 mm × 4.6 mm) was comparatively studied against two conventional reversed-phase silica-based and one monolithic column. Eight antimicrobial agents representing two different classes: penicillins and amphenicols, were separated using a typical 400 bar high performance liquid chromatography (HPLC) equipment. Comparison of column performance was carried out by calculation of the number of theoretical plates N, the tailing factor Tf, the relative retention time RRT, the retention factor k, the resolution factor Rs, and the precision of the retention time and peak area. Optimal chromatographic conditions were used to validate the method. Its applicability was proven by the analysis of veterinary drug formulations. The examined antibiotics were well resolved within 17 min. Limit of quantitation values were 25.9 ng for amoxicillin, 14.1 ng for ampicillin, 41.6 ng for thiamphenicol, 9.6 ng for oxacillin, 23.5 ng for florfenicol, 26.7 for cloxacillin, 23.5 ng for chloramphenicol and 42.3 ng for dicloxacillin for 20 µL injection volume. The developed method can be easily and readily transferred to any laboratory. Copyright © 2010 John Wiley & Sons, Ltd.

A new analytical method based on CZE coupled with tandem MS detection (CE-MS/MS) has been developed for the simultaneous determination of nine penicillins of human and veterinary use (nafcillin, dicloxacillin, cloxacillin, oxacillin, ampicillin, penicillin G, amoxicillin, penicillin V and piperacillin), whose levels are regulated by the EU Council regulation No. 2377/90 in animal edible tissues. CE separation conditions, sheath liquid composition and electrospray parameters have been carefully optimized to reach high sensitivity and precision. Separation was carried out in a 96 cm total length fused-silica capillary (50 microm id, 360 microm od) using 60 mM ammonium acetate at pH 6.0 as running buffer. Lomefloxacin was used as internal standard. MS/MS experiments were carried out using an IT as analyzer operating in multiple reaction monitoring mode to achieve the minimum number of identification points established by the 2002/657/EC European Decision. The use of an SPE procedure in two steps, combining Oasis hydrophilic-liphophilic balance and Alumina N cartridges provide a satisfactory preconcentration and clean up treatment for meat samples after extraction of the compounds with ACN. Only Oasis hydrophilic-liphophilic balance cartridges were necessary in water samples to obtain adequate recoveries. The method has been characterized for its use in meat and water samples, using matrix-matched calibrations. For chicken muscle samples, LODs between 8 and 12 microg/kg have been obtained, in all cases lower than the maximum residue limits permitted. For water samples LODs from 0.18 to 0.26 microg/L could ensure its satisfactory application in aquatic samples.

Study Objective. To determine whether upregulation of P-glycoprotein is responsible for the enhanced renal clearance of dicloxacillin in patients with cystic fibrosis. Design. Single-center, prospective, open-label, randomized, three-part crossover pharmacokinetic study. Setting. General clinical research center. Subjects. Eleven patients with cystic fibrosis and 11 age-matched healthy volunteers. Intervention. All subjects received a single oral dose of dicloxacillin 500 mg alone, dicloxacillin 500 mg plus probenecid (an organic anion transport inhibitor) 1 g, and dicloxacillin 500 mg plus cyclosporine (a P-glycoprotein inhibitor) 5 mg/kg; each treatment was separated by a washout period of 48 hours. A bolus dose of iothalamate meglumine 456 mg was administered on each study day as a marker of glomerular filtration. Measurements and Main Results. Blood and urine samples were taken serially up to 6 hours after each dose. Pharmacokinetics of dicloxacillin and iothalamate were determined by using compartmental and noncompartmental methods. Quantitative polymerase chain reaction was performed on peripheral blood mononuclear cells to measure expression of multidrug resistance 1 (MDR1) messenger RNA (mRNA). Genotyping for ABCB1 was performed to determine the presence of single nucleotide polymorphisms (exons 21 and 26). In both healthy subjects and patients with cystic fibrosis, compared with dicloxacillin alone, coadministration with probenecid produced a significantly lower renal clearance of dicloxacillin, whereas coadministration with cyclosporine resulted in no significant change; renal clearance was not significantly different between the two study groups. No correlation was found between MDR1 mRNA expression and renal clearance of dicloxacillin. The renal excretion of dicloxacillin was significantly greater in subjects with the ABCB1 exon 26 TT polymorphism when compared with subjects with the CT genotype. Conclusion. We found no significant difference in the pharmacokinetics of dicloxacillin between patients with cystic fibrosis and healthy volunteers. Renal clearance of dicloxacillin was significantly reduced in the presence of probenecid but not with cyclosporine, suggesting that the rate-limiting step in tubular secretion of dicloxacillin is uptake mediated by the organic anion transporter, and not P-glycoprotein inhibition.

A method for the simultaneous determination of eight beta-lactam antibiotics (nafcillin, cloxacillin, oxacillin, dicloxacillin, ampicillin, amoxicillin, and penicillin G) in fortified milk samples of different origins has been proposed by using CZE with diode-array detection (CZE-DAD). Optimum separation was obtained on a 64.5 cm x 75 microm bubble cell capillary using 175 mM Tris buffer with 20% ethanol at pH 8.0. Methylparaben has been used as an internal standard (IS). Taking into account the lack of sensitivity of the UV-Vis detection, a solvent extraction/SPE method was applied for off-line preconcentration and sample cleanup, and also an on-line preconcentration methodology, such as large-volume sample stacking (LVSS) with polarity switching, was developed, providing LODs ranging from 2 to 10 microg/L. The method permits the quantification of these residues below the levels established in milk by the EU Regulation. Satisfactory recoveries ranging from 86 to 93% were also obtained in milk samples of different origins.

A quantitative method for the determination of four penicillin antibiotics, amoxicillin (AMO), oxacillin (OXA), cloxacillin (CLO), and dicloxacillin (DICLO), has been developed. Separation was achieved on an Inertsil ODS-3 (250 x 4 mm, 5 microm) column after selective extraction of penicillin drugs from biological matrices by means of SPE. Gradient elution with a mobile phase consisting of 0.1% TFA (pH 1) and ACN, and PDA detection with monitoring at 240 nm was applied. Salicylic acid (5 ng/microL) was used as the internal standard. RP-8 Adsorbex Merck cartridges provided high absolute recoveries (98-101%). The developed method was fully validated in terms of selectivity, linearity, accuracy, precision, stability, and sensitivity. Repeatability (n = 8) and between-day precision (n = 8) revealed RSD

A 30-year-old woman presented with a 7-day history of multiple erythematous and purple plaques (1–3 cm in diameter) on her abdomen. She was a postpartum housewife attending a gymnasium where 15 d before she had received subcutaneous mesotherapy with silica, triiodoacetic acid, and artichoke oil to improve her pendulous abdomen. One week after, on the sites of the procedure, she detected painful lesions draining yellowish exudate (Fig. 1). She was treated with dicloxacillin 500 mg every 6 h and diclofenac 100 mg every 12 h for 7 d without improvement. Atypical mycobaterial infection secondary to mesotherapy was suspected; therefore, a biopsy, cultures, and smears were performed. Biopsy showed a suppurative granulomatous dermatitis (Fig. 2), but no microorganisms were visualized with Ziehl–Neelsen, Gomori–Grocott, or periodic acid-Schiff stains. Nocardia spp., was isolated on Sabouraud dextrose agar (Fig. 3) and N. brasiliensis was identified by molecular biology. Molecular identification was carried out by sequencing 16S rRNA. Genomic DNA was isolated using a DNeasy blood and tissue kit (Qiagen, Ventura, CA, USA) according to the manufacturer’s instructions. The polymerase chain reaction product was purified using a QIAquick PCR Purification Kit (Qiagen, La Jolla, CA, USA) as recommended by the suppliers. Nucleotide sequence was determined in both directions with Taq FS Dye Terminator Cycle Sequencing Fluorescence-Based Sequencing and analyzed on a Perkin Elmer/Applied Biosystems (Foster City, CA, USA) 3730 DNA sequencing system. The sequences showed 100% identity with N. brasiliensis CDC :W7503. The complete sequence obtained 888 Figure 1 Multiple erythematous and purple plaques, 1–5 cm of diameter

The irritating effect of parenterally administered antibiotics on vessels is a common clinical problem. In a previous study we found that solutions of three commonly used antibiotics, cefuroxime, erythromycin and dicloxacillin, exerted cytotoxic effects on endothelial cells after 24 hr exposure. In contrast benzylpenicillin did not have such effects. In the present study, endothelial cells of different origin were exposed to these four antibiotics at higher concentrations than in the previous investigation but only for 5, 30 and 60 min. Incorporation of 3H-thymidine in the cells as a measurement of DNA synthesis was used as cytotoxic assay. A concentration-dependent and time-related inhibition was found after exposure to erythromycin and dicloxacillin but not after exposure to cefuroxime and benzylpenicillin. The effects were similar on the three different cell types used in the experiments. This study demonstrates that the cytotoxic effects differ even after short-term exposure to the antibiotics. In contrast to the previous study, cefuroxime lacks cytotoxicity when endothelial cells are exposed for less than one hour. The short-term exposition model used in this study should be more predictive as it mimics in vivo conditions better.

A 34-year-old man presented with a pubic eruption of 4 weeks duration, affecting both himself and his partner. He had been treated unsuccessfully with intravenous and oral dicloxacillin. The eruption was a severely inflammatory folliculitis, with haemo-serous exudate and marked oedema. A clinical diagnosis of herpes simplex virus folliculitis was disproved when routine bacteriology isolated Aeromonas hydrophila and multiple viral polymerase chain reaction studies were negative. Histology demonstrated a chronic folliculitis with no organisms present. Both he and his partner were treated with oral ciprofloxacin 500 mg bd for 6 weeks with clinical clearance of infection, but both developed a scarring alopecia. Infection was attributed to possible contamination of a poorly maintained home spa bath with A. hydrophila.

Intravenous administration of antibiotics often causes local pain and thrombophlebitis at the site of injection. An in vitro model that could predict these effects would be of great value. In this study the effects of four antibiotics, benzylpenicillin, cefuroxime, dicloxacillin and erythromycin, have been evaluated on three types of endothelial cells in culture. The cell types employed were primary culture from human umbilical vein, primary culture from bovine aorta, and the cell line EA-hy 926, a hybride endothelial cell. These cells were exposed to antibiotics for 24 hr and subsequently toxic effects on cells were evaluated by three different assays. Benzylpenicillin was atoxic in all types of cells and in all assays, in contrast to the other antibiotics. The other three antibiotics exerted dose dependent toxic effects in all investigated cells when DNA-synthesis and total cell protein were used as toxicity assays but the results varied between the cell types. There were no significant differences between the effects of cefuroxime, dicloxacillin and erythromycin on bovine endothelial cells. In the other cell types, however, there were significant differences between some drugs but the outcome depended on the cell type. It is concluded that it is possible to show differences between the effect of antibiotics on endothelial cells, but the result depends on the cell type employed.

Reduction in the dosage of dicloxacillin from 500 mg to 250 mg 3 times a day would mean lowering of costs and less side-effects in orthopaedic infections. In this cross-over study, the serum concentrations of dicloxacillin were measured in 9 patients after administration of dicloxacillin 500 mg 3 times a day (dicloxacillin 500 mg) and after co-administration of 250 mg dicloxacillin and 250 mg probenecid 3 times per day (dicloxacillin 250 mg+probenecid 250 mg). Concentrations were measured every hour after the tablet intake. The mean maximum serum concentrations of dicloxacillin were 17.1 micrograms/ml (dicloxacillin 500 mg) and 12.2 micrograms/ml (dicloxacillin 250 mg+probenecid 250 mg), respectively (P < 0.05). Serum concentrations above 3 micrograms/ml were obtained during 285 min. in both regimes, but the individual variations were biggest during in the dicloxacillin 250 mg+probenecid 250 mg treatment. Serum concentrations above 5 micrograms/ml were in mean measured during 228 min. (dicloxacillin 500 mg) and 190 min. (dicloxacillin 250 mg+probenecid 250 mg), respectively (P < 0.05). The clinical significance of these findings is being discussed. In theory, treatment with dicloxacillin 250 mg+probenecid 250 mg may be as sufficient as dicloxacillin 500 mg.

A 52-year-old black woman presented with a 2-day history of lower lip swelling 5 days after starting a new medication, lisinopril. She had never experienced similar episodes in the past. She denied shortness of breath, tightening of the throat, swelling of the tongue, generalized cutaneous eruption, urticaria, or pruritus. She also denied symptoms consistent with facial paresis. Her past medical history was significant for hepatitis C infection, coronary artery disease, and hypertriglyceridemia. She had a 15 pack-year smoking history and denied both alcohol and drug abuse. She had never received a blood transfusion and was HIV negative. Physical examination disclosed a tender, swollen, and erythematous lower lip with induration, oozing, and crusting (Figure 1). Pinpoint openings evident throughout the lip surface exuded a clear, sticky, mucoid secretion. Tongue, parotid glands, and regional lymph nodes were normal. The working diagnosis was angioedema secondary to lisinopril. The presumptive offending drug was discontinued, and conservative therapy (topical clobetasol ointment, oral ranitidine, and oral fexofenadine) was initiated. Despite treatment, signs and symptoms persisted unabated. One week after initial presentation, a punch biopsy of her lower lip was taken to rule out granulomatous cheilitis and sarcoidosis. Histopathology included diffuse lymphohistiocytic infiltrate, minimal microabscess formation, and notable absence of granulomata. There was neither hypertrophy nor detectable abnormality of the salivary glands, with the exception of infiltrating mononuclear cells. Based on the clinical history and compatible pathologic findings, a diagnosis of cheilitis glandularis was made. Specifically, crusting and erosion clinically suggested a diagnosis of the superficial suppurative subtype of cheilitis glandularis. The patient received oral penicillin (dicloxacillin, 1.0 g/d) combined with oral fluoroquinolone (ciprofloxacin, 1.0 g/d). Within 2 weeks of starting the antibiotics, the lip swelling significantly decreased (Figure 2) and the patient was left with a mildly indurated nodule at the labial commissure. Following a 4-week course of continued antibiotic treatment, the lip returned to near baseline state. At both 6-month and 1-year follow-up visits, the lip remained normal.

Two children with staphylococcal blistering distal dactylitis (BDD), a condition usually caused by streptococci, are reported. Etiologic distinction in BDD can be made only bacteriologically. Staphylococci are increasingly the cause of bacterial cutaneous infections.

We studied the microbiological efficacy of antibiotics on skin infections using experimentally induced skin infection in hamsters. Topical gentamicin (GM), intramuscular injection of GM and oral administration of cephalexin (CEX) were used in hamsters against experimentally induced staphylococcal skin infections. Effects were studied as a function of the dose of cephaloridine (CER) injected intramuscularly at a fixed daily frequency. Effects were also studied as a function of the daily frequency of intramuscular injection of CER at a fixed dose. We found no marked differences in the efficacy of topical application, intramuscular injection, and oral administration. In the dosage study, there were no differences in the efficacy when CER was used at the dosage of 20 mg/kg or more. No differences were found in efficacy when CER was injected twice or more times a day. Topical antibiotic treatment has limitations in the management of skin infection. Skin has a moderate repair activity, so an antibiotic can produce a good clinical course even at a lower concentration than the MIC against a causative organism. The antibiotics studied could give constant efficacy when administered at appropriate doses at fixed frequency or in appropriate frequencies at a fixed dosage.

A total of 54 Staphylococcus aureus strains of varying methicillin resistance were investigated for their resistance to methicillin, oxacillin and dicloxacillin by different diffusion tests. Inhibition zones were measured around locally prepared paperdiscs with 10 micrograms methicillin, 5 and 10 micrograms oxacillin, 5 and 10 micrograms dicloxacillin, PDM paperdiscs with 10 micrograms methicillin or oxacillin and Neo-sensitabs tablets with methicillin or oxacillin. All diffusion tests were performed both with Mueller-Hinton agar and Danish Blood agar as well as at 37 degrees C and 30 degrees C and read after overnight incubation. Differences in zone diameter under different conditions were found to be independent of the susceptibility level of the strains. Seventeen of the strains were detected as methicillin-resistant (MRSA) by two methods including high inoculum and prolonged incubation at 30 degrees C. The minimum inhibitory concentration (MIC) of the 54 strains was determined by a plate dilution method at 30 degrees C and 37 degrees C. A 10 micrograms locally prepared methicillin disc detected all MRSA strains with no false reactions either at 37 degrees C or 30 degrees C on Mueller-Hinton agar. Investigations with oxacillin discs had to be performed at 30 degrees C or with a 5 microgram disc in order to detect correctly. PDM paperdiscs gave reactions identical to the corresponding locally prepared discs. Methicillin Neo-sensitabs detected all MRSA strains but also included a few susceptible strains among the resistant ones. Addition of blood increased the number of not-detected MRSA strains. All 17 MRSA strains were susceptible to dicloxacillin by the dilution method, and the disc diffusion test showed similar results. Dicloxacillin discs therefore did not detect the presence of MRSA strains. The implications of replacement of the methicillin/oxacillin disc by a dicloxacillin disc are discussed.

A synthesis of potassium [14C] dicloxacillin, labelled in the 3-position of the isoxazole ring, is described. The compound, having the specific activity 21 mCi/mmole, was obtained in 30% overall yield from ethyl [3-14C] acetoacetate.

Effects of penicillins on the binding of phenytoin to plasma proteins were examined in vitro and in vivo. The results from in vitro studies showed that the penicillins including oxacillin and dicloxacillin were effective in displacing phenytoin from its binding sites. In vivo, the total phenytoin concentration in serum decreased during penicillin administration, while the free phenytoin concentration increased. As a result, penicillins caused a significant increase in the apparent volume of distribution and in the total body clearance of phenytoin. These results can be explained on the basis of the displacement of phenytoin from its plasma protein binding site by penicillins.

A series of compounds were found to be effective in vitro inhibitors of serum protein binding of penicillins G, V, ancillin, nafcillin, oxacillin, cloxacillin, and dicloxacillin when used at a molar concentration of 1 x 10−3 versus the penicillins at 1 x 10−4 M. Three of these compounds, sulfamethoxypyridazine, sulfaethylthiadiazole, and acetylsalicylic acid were employed in volunteer studies to determine their effect on serum concentrations and binding of the various penicillin analogues in vivo. it was possible to reduce serum binding of the penicillins in man by this approach with all of the penicillin analogues studied, including the very highly bound drug, dicloxacillin. When effective, binding inhibitors tended to lower concentrations in serum of total penicillin and in almost all instances significantly increased the concentrations of unbound antibiotic. Sulfonamides interfered with the oral absorption of oxacillin. The limitations of this approach to current therapy with penicillins are presented together with a brief description of the features of a desirable new penicillin analogue.

Flucloxacillin is a new isoxazolyl penicillin active in vitro against gram-positive cocci. Of 190 clinical isolates of Group A s-hemolytic streptococci, pneumococci and both penicillin G-sensitive and penicillin G-resistant Staphylococcus aureus, were inhibited by 0.78 µg per milliliter or less of isoxazolyl penicillin. Mean peak serum levels in normal volunteers following the oral administration of 250 mg. and 500 mg. of flucloxacillin were 5.7 and 11.4 µg per milliliter, respectively. The mean peak serum level was 11.8 µg per milliliter following the intramuscular administration of 250 mg. of flucloxacillin. Serum levels with flucloxacillin wMe lower than those obtained with dicloxacillin, but greater than those with cloxacillin. Flucloxacillin was 92.6 per cent bound to human serum proteins and provided higher serum levels of free drug than the other isoxazolyl penicillins.