Search

Introduction: Intramuscular benzathine penicillin G (BPG) injections are a cornerstone of secondary prophylaxis to prevent acute rheumatic fever (ARF) and rheumatic heart disease (RHD). Uncertainties regarding inter-ethnic and preparation variability, and target exposure profiles of BPG injection are key knowledge gaps for RHD control., Methods: To evaluate BPG pharmacokinetics (PK) in patients receiving 4-weekly doses in Ethiopia, we conducted a prospective cohort study of ARF/RHD patients attending cardiology outpatient clinics. Serum samples were collected weekly for one month after injection and assayed with a liquid chromatography-mass spectroscopy assay. Concentration-time datasets for BPG were analyzed by nonlinear mixed effects modelling using NONMEM., Results: A total of 190 penicillin concentration samples from 74 patients were included in the final PK model. The median age, weight, BMI was 21 years, 47 kg and 18 kg/m2, respectively. When compared with estimates derived from Indigenous Australian patients, the estimate for median (95% confidence interval) volume of distribution (V/F) was lower (54.8 [43.9-66.3] l.70kg-1) whilst the absorption half-life (t1/2-abs2) was longer (12.0 [8.75-17.7] days). The median (IQR) percentage of time where the concentrations remained above 20 ng/mL and 10 ng/mL within the 28-day treatment cycle was 42.5% (27.5-60) and 73% (58.5-99), respectively., Conclusions: The majority of Ethiopian patients receiving BPG as secondary prophylaxis to prevent RHD do not attain target concentrations for more than two weeks during each 4-weekly injection cycle, highlighting the limitations of current BPG strategies. Between-population variation, together with PK differences between different preparations may be important considerations for ARF/RHD control programs., Competing Interests: The authors have declared that no competing interests exist.

Objective: To compare maternal and cord blood penicillin concentrations in women with and without obesity who are receiving intrapartum group B streptococcus (GBS) prophylaxis., Methods: We performed a prospective cohort study of term women receiving intrapartum penicillin prophylaxis for GBS colonization (determined by antenatal rectovaginal culture). The following outcomes were compared between obese (body mass index [BMI] 35 or higher at delivery) and nonobese (BMI less than 30 at delivery) groups: penicillin concentration in maternal blood (after two penicillin doses) and umbilical cord blood, GBS rectovaginal colonization status on admission and after two completed doses, and neonatal GBS colonization (using a postnatal ear swab). Fifty-five women were needed to detect a 0.75 SD difference in cord blood penicillin concentrations., Results: Fifty-five women were enrolled and had all specimens collected; 49 had complete data for analysis (obese n=25, nonobese n=24). There was no difference in the median maternal penicillin concentration between groups (obese 4.2 micrograms/mL vs nonobese 4.0 micrograms/mL, P=.58). There was, however, a 60% lower median cord blood penicillin concentration in the obese compared with the nonobese group (2.7 micrograms/mL vs 6.7 micrograms/mL, respectively, P<.01), with no significant difference in time from last penicillin dose to delivery (obese 2.9 hours vs nonobese 1.7 hours, P=.07). The difference in cord blood concentrations remained significant after adjustment for nulliparity, hypertensive disorders, and time from last penicillin dose to delivery. Only 59.6% of women tested positive for GBS by rectovaginal culture on admission (obese 60.9% vs nonobese 58.3%, P=.86)., Conclusion: The median cord blood penicillin concentration was 60% lower in neonates born to women with obesity compared with those born to women without obesity. However, all concentrations exceeded the minimum inhibitory concentration. Maternal penicillin levels were not significantly different between groups. More than 40% of women who previously tested positive for GBS by antenatal culture tested negative for GBS on admission for delivery.

Temocillin is a β-lactamase-resistant penicillin used for the treatment of multiple drug-resistant Gram-negative bacteria. To maximize efficacy and avoid adverse effects, the dose regimen has to be quickly adjusted to the clinical situations. This necessitates the development of a rapid, reliable and accurate analytical method. Temocillin and the stable isotopically labeled internal standard ([ 13 C 6 ]-amoxicillin) were extracted from either serum or cerebrospinal fluid by a turbulent flow liquid chromatographic method and eluted onto an octadecyl-silica phase with polar endcapping. Mass spectrometry was conducted using an exact mass determination method by electrospray positive ionization high-resolution mass spectrometry. The LLOQ and ULOQ of the present method were determined to be 0.4 and 200 μg/ml for serum and cerebrospinal fluid samples, respectively. The total analysis time was <7 min. The recovery ranged from 87.7 to 120.8%. Intra- and inter-day precision and trueness were tested at four concentration levels: 0.4, 8, 40 and 160 μg/ml. Values were 6.33 ± 1.53, 8.8 ± 1.3, 8.8 ± 0.36 and 2.1 ± 0.76%, and 5.0 ± 0.54, 9.9 ± 1.0, 5.8 ± 1.6 and 0.1 ± 1.1%, for inter- and intra-day analysis, respectively. Temocillin was found to be stable under all relevant laboratory conditions. The method was cross-validated with a microbiological assay. This method is suitable for accurate measurement of temocillin concentration in small volumes of serum or cerebrospinal fluid. Thanks to the online extraction procedure, the overall analytical time is compatible with high-throughput analysis for clinical application., (© 2019 John Wiley & Sons, Ltd.)

Penicillin is administered intravenously (IV) or intramuscularly (IM) to horses for the prevention and treatment of infections, and both routes have disadvantages. To minimize these shortcomings, a 24-hr hybrid administration protocol (HPP) was developed. Our objective was to determine penicillin plasma concentrations in horses administered via HPP. Venous blood was collected from seven healthy horses administered IV potassium penicillin G at 0 and 6 hr and IM procaine penicillin G at 12 hr. Blood was collected at 2-hr intervals from 0 to 20 hr and at 24 hr. Plasma penicillin concentrations were measured using liquid chromatography and mass spectrometry. Penicillin susceptibility from equine isolates was examined to determine pharmacodynamic targets. The MIC 90 of penicillin for 264 isolates of Streptococcus sp. was ≤0.06 μg/ml. For the 24-hr dosing interval, the mean plasma penicillin concentration was >0.07 μg/ml. Five horses (72%) exceeded 0.06 μg/ml for 98% of the dosing interval, and two horses exceeded this value for 52%-65% of the dosing interval. The HPP achieved mean plasma penicillin concentrations in healthy adult horses above 0.07 μg/ml for a 24-hr dosing interval. However, individual variations in plasma concentrations were apparent and deserve future clinical study., (© 2018 John Wiley & Sons Ltd.)

Objectives: The aim of this study was to develop and validate a HPLC-MS/MS assay to determine total and unbound concentrations of temocillin in serum samples., Design and Methods: Methanolic protein precipitation and ultrafiltration were used for total and unbound concentration extraction, respectively. Extract was injected into a LC-MS/MS system. Reversed phase chromatography was performed on a phenyl grafted column in gradient mode. Temocillin and internal standard (ticarcillin) were identified in positive electrospray ionization mode using ion transitions of m/z 415.34>339.1 and 385.31>160.3, respectively., Results: Temocillin total and unbound concentration quantification assays were linear over concentrations ranging from 1 to 500 mg/L and from 0.5 to 300 mg/L, respectively. Both assays presented acceptable intra and inter-assay precision and accuracy <13.9%. Limits of quantification and detection were of 1 and 0.10mg/L, and 0.5 and 0.05 mg/L for total and unbound concentration respectively. Total temocillin concentration recovery ranged from 85.80 to 99.40%. Temocillin ion suppression effect was <36.2 % in both assays., Conclusion: The method described is fast, sensitive and selective, with no interferences. This method may be used for both pharmacokinetic studies and therapeutic drug monitoring purposes., (Copyright © 2015 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Background: Antibiotic prophylaxis treatment at delivery is highly recommended for reducing the risk of infection for mothers positive for group B streptococcus. It is therefore expected that some cord blood (CB) products will contain residual antibiotics. This study aimed to determine the incidence and level of β-lactam antibiotics in CB products., Study Design and Methods: The antimicrobial activity of 60 CB plasma by-products was evaluated using disk diffusion assays on 10 bacteria species. Plasma samples showing antimicrobial activity were either treated with β-lactamase enzyme to inhibit β-lactam antibiotics or heated to 56°C for 30 minutes to inhibit complement proteins. β-Lactam antibiotic concentrations were determined by comparison with a standard curve obtained with known concentrations of antibiotics., Results: Antimicrobial activity against mostly Gram-positive microorganisms was observed in 33% of CB units. The β-lactamase enzyme abolished the antimicrobial activity in the majority of these CB products. Up to 5 μg/mL penicillin and 14 μg/mL ampicillin were measured in these products., Conclusion: Approximately one-third of CB products contain significant amounts of plasma with residual antibiotics, which can affect the survival and growth of bacterial contaminants when performing the sterility test and potentially lead to false-negative results. Additional work is required to better understand whether residual antibiotics in CB affect penicillin-allergic patients., (© 2014 AABB.)

Antibiotics are most commonly prescribed drugs in clinical practice. Therapeutic drug monitoring of these medications is typically associated with a select group of antibiotics such as aminoglycosides and vancomycin. Outside this group, other antibiotics such as chloramphenicol and antituberculosis agents may also require monitoring. Due to their wide therapeutic index, other classes of antibiotics such as penicillins, cephalosporin, sulfonamides, quinolones, and macrolides do not generally require routine therapeutic drug monitoring. Determination of serum or plasma concentration of these drugs, however, may be beneficial in those patients with compromised renal function. As can be expected, immunoassays for routine monitoring of aminoglycosides and vancomycin have been developed and are widely commercially available. Tests for other antibiotics, due to their infrequent use and low clinical application, are generally limited to in-house developed methods.

Herein a quantitative method for the determination of seven penicillins in bovine plasma and veterinary drugs has been developed. Amoxicillin (AMO), ampicillin (AMP), penicillin G (PENG), penicillin V (PENV), oxacillin (OXA), cloxacillin (CLO) and dicloxacillin (DICLO) were separated on a Perfectsil ODS-2 (250 x 4 mm, 5 microm) column, using gradient elution, with a mobile phase of 0.1% v/v TFA and ACN-methanol (90:10 v/v). PDA detection was used at 240 nm. Penicillins were isolated from bovine plasma by SPE on Lichrolut RP-18 cartridges with mean recoveries from 85.7 to 113.5%. Colchicine (3 ng/microL) was used as an internal standard. The developed method was validated in terms of selectivity, linearity, accuracy, precision, stability and sensitivity. Repeatability (n = 5) and between-day precision (n = 5) revealed RSD < 12%. The detection limits in the bovine plasma were estimated as 18 ng for AMO and AMP, 25 for PENG, PENV and OXA, 3 ng for CLO and 12 ng for DICLO. Spiked plasma samples were stable for 1 wk, except for AMP and CLO, which were stable for 3 wk and OXA for 4 wk. AMO, PENG and PENV were stable for two freeze-thaw cycles, OXA, CLO and DICLO for four, while AMP only for one.

A RP-HPLC method with rapid sample processing was developed for quantitation of flucloxacillin in human plasma using dicloxacillin as the internal standard. The plasma sample (100 microL) was acidified with glacial acetic acid, and deproteinized by precipitation with acetonitrile. The supernatant was directly injected into the HPLC system. Separation was achieved on an Alltima C18 column (250 mmx4.6 mm I.D., 5 microm), with a mixture of 10 mmol x L(-1) KH2PO4-acetonitrile (64.5:35.5, v/v) as mobile phase. The assay was successfully applied to a randomized, two-period cross-over bioequivalence study in 20 healthy Chinese volunteers following a single oral dose of 250 mg flucloxacillin capsules. A non-compartmental method was used for pharmacokinetic analysis. Compared with data in the literature, flucloxacillin was eliminated more slowly in Chinese than in Caucasians. Cmax, AUC(0-t) and AUC(0-infinity) were tested for bioequivalence after log-transformation of data. No significant difference was found. Tmax was analyzed by Wilcoxon's test and no significant difference was obtained (P > 0.05). Based on these statistical inferences, the two formulations were judged to be bioequivalent and, thus, can be prescribed interchangeably.

Natural penicillin (benzylpenicillin) is the oldest antibiotic observed by Alexander Fleming in 1928. To broaden its spectrum of activity, natural penicillin was modified, giving rise to a group of antibiotics under the name 'penicillins'. Although an increasing number of bacteria appear to be resistant to them, penicillins are used to treat a variety of bacterial infections including Gram-positive, Gram-negative aerobic and anaerobic bacteria. Consequently, they are widely used in human and veterinary medicine to prevent and treat diseases. This review covers the analytical methodologies, mainly chromatographic, employed to the penicillins determination in pharmaceutical formulations, biological fluids and in production-scale fermentations reported in the literature. Results of published assays are comparatively presented focusing on sample preparation regarding isolation and purification, chromatographic conditions and method validation. Information on chemical structure, spectrum of activity and action mechanism of common penicillins has also been given.

Objectives: To compare the in vitro and in vivo activity of penicillin, cefotaxime and ceftriaxone, using three strains of Streptococcus pneumoniae with different susceptibilities to penicillin (MICs of 0.015, 0.25 and 2 mg/L, respectively)., Methods: Time-kill curves and an experimental model of endocarditis in rabbits., Results: Penicillin was efficacious in clearing bacteria from vegetations and blood irrespective of whether infections were caused by penicillin-susceptible or penicillin-resistant strains (P < 0.01 with respect to control groups). The same efficacy was shown with cefotaxime and ceftriaxone. Comparing the results of the in vivo model with those obtained in time-kill curves, penicillin showed the best results., Conclusions: These results confirm that penicillin is efficacious in the treatment of pneumococcal infections, including those produced by strains with MICs < or = 2 mg/L (with the exception of pneumococcal meningitis). These results also suggest that the breakpoints to define susceptibility and resistance of S. pneumoniae to penicillin must be reviewed, as has been done with amoxicillin and third-generation cephalosporins.

A sensitive and selective method for the simultaneous determination of carvedilol and ampicillin sodium (AS) in the presence of human serum albumin (HSA) is described. The maximum emission wavelengths of carvedilol and AS are at 357 nm and 426 nm with excitation at 254 nm, respectively. The first-derivative peaks of carvedilol and AS were at 337 nm and 398 nm, respectively. The linear-regression equations of the calibration graphs of carvedilol and AS were C = 0.0001H - 0.0063 and C = 1.530H - 43.84; the correlation coefficients were 0.9990 and 0.9986, respectively. The detection limits were 1 ng ml(-1) for carvedilol and 23 microg ml(-1) for AS, respectively. The effects of the pH, the stability of carvedilol and AS and foreign ions on the determination of carvedilol and AS were examined. The recoveries of carvedilol and AS were measured. This method is simple and can be used for the determination of carvedilol and AS in human serum and urine samples with satisfactory results.

The possible reactivities of commonly used antibiotics of fungal, nonfungal, and nonmicrobial or synthetic sources with the Platelia Aspergillus galactomannan assay were assessed. For drugs that tested positive, the minimal concentration of the antibiotic in serum that yielded a positive test (index, >0.5) was determined. At undiluted concentrations, piperacillin and multiple lots of piperacillin-tazobactam tested positive, whereas amoxicillin, ampicillin-sulbactam, nafcillin, cefazolin, ceftazidime, erythromycin, gentamicin, and levofloxacin tested negative. All three lots of piperacillin-tazobactam and all bags within each lot tested positive, with a mean index value of 5.168. At achievable concentrations in serum, however, only one of three lots of piperacillin-tazobactam yielded a positive test. Concentrations of 75, 150, and 300 microg/ml of serum tested positive with the Platelia Aspergillus enzyme immunoassay, whereas lower concentrations, mimicking the trough levels, tested negative. Thus, while achievable serum piperacillin-tazobactam concentrations may potentially result in a positive test for galactomannan, the timing of the collection of serum samples from patients may influence the test results, with reactivity being less likely in samples collected at trough levels or prior to the administration of a dose of the antibiotic.

Aims: Nafcillin (Wyeth Laboratories, Philadelphia, PA, USA) has been reported to induce the metabolism of cyclosporin and warfarin, which are known substrates of cytochrome P-450 (CYP). However, there has not been any report to date on its possible interaction with nifedipine, an index substrate of the enzyme, CYP3A4., Methods: Nine healthy normotensive subjects participated in this randomized placebo-controlled two-way crossover study examining the effects of 5 days' pretreatment of nafcillin 500 mg or placebo four times daily on the pharmacokinetics of an oral dose of nifedipine 10 mg. Plasma nifedipine concentrations were measured by gas chromatography-mass spectro., Results: The area under the plasma nifedipine concentration-time curve (AUC0-alpha) in nafcillin-pretreated subjects (80.9 +/- 32.9 micro g l-1 h-1) was significantly decreased compared with subjects who received only nifedipine (216.4 +/- 93.2 micro g l-1 h-1) (P < 0.001). Total plasma clearance of nifedipine (CL/F) was significantly increased with nafcillin pretreatment (138.5 +/- 42.0 l h-1 vs 56.5 +/- 32.0 l h-1) (P < 0.002)., Conclusions: The results show that nafcillin pretreatment markedly increased the clearance of nifedipine and suggest that nafcillin is a potent inducer of CYP enzyme.

Purpose: An accurate, precise and sensitive HPLC assay was developed for the determination of amoxicillin in human plasma samples, to compare the bioavailability of two amoxicillin capsule (500mg) formulations (Amoxicilina from Brazil, as a test formulation and Amoxil from SmithKline Beecham Laboratories Ltda., Brazil, as a reference formulations) in 24 volunteers of both sexes., Methods: Amoxicillin concentrations were analyzed by combined reversed phase liquid chromatography and UV detection (lambda=229 nm). Amoxicillin and cefadroxil (internal standard) were extracted from the plasma by addition of cold methanol. The separation was achieved using the Lichrosorb 10 microm, C18 reversed phase column at room temperature. The mobile phase consisted of a 95% phosphate buffer (0.01 mol/L), pH=4.8 and 5% acetonitrile mixture. The study was conducted using an open randomized 2-period crossover balanced design with a 1-week washout period between the doses. Plasma samples were obtained over an 8-hour period. The bioequivalence between the two formulations was assessed by calculating individual peak plasma concentrations (C(max) ) and area under the curve (AUC(0-8h) ) ratios (test/reference). The statistical interval proposed was 80-125%, as established by the US Food and drug administration Agency., Results: The internal standard and amoxicillin eluted about 4.2 and 5.2 min, respectively at a flow rate of 1.3ml/min. The mean absolute recovery of AMO in plasma was 90.0% at 3 microg/ml, 98.6% at 25 microg/ml and 95.3 at 50 microg/ml. The assay showed excellent relationships between peak height ratios and plasma concentrations (r(2)>or= 0.999). The limit of quantification was 1g/ml, based on 200l of plasma. The geometric mean of Amoxicilina/Amoxil 500 mg capsules individual percentage ratio was 101.4% for AUC(0-8h), and 99.9% for C(max). The 90% confidence intervals were 98.3-104.4% and 95.7-103.9%, respectively., Conclusion: This simple, rapid and selective method is suitable for pharmacokinetic, bioavailability and bioequivalence studies. Since the 90% CI for both C(max )and AUC(0-8h) lies within the 80-125% interval proposed by the Food and Drug Administration, it was concluded that Amoxicilina 500 mg capsules was bioequivalent to Amoxil capsules 500 mg, in terms of both the rate and extent of absorption.

Background: Flucloxacillin is an important antimicrobial drug in the treatment of infections with Staphylococcus aureus and therefore is often used in staphylococcal infections. Furthermore, flucloxacillin has a high protein binding rate as for example ceftriaxone or teicoplanin--drugs which have formerly been characterized as not being dialyzable., Methods: The pharmacokinetic parameters of 4.0 g flucloxacillin every 8 h were examined in 10 intensive care patients during continuous venovenous hemofiltration (CVVH) using a polyamide capillary hemofilter. In addition, the difficulty of calculating the hemofiltration clearance of a highly protein-bound drug is described., Results: Flucloxacillin serum levels were significantly lowered (56.9 +/- 24.0%) even though only 15% of the drug was detected in the ultrafiltrate. Elimination half-life, total body clearance and sieving coefficient were 4.9 +/- 0.7 h, 117.2 +/- 79.1 ml/min and 0.21 +/- 0.09, respectively. These discrepancies can be explained by the high protein binding of flucloxacillin, the adsorbing property of polyamide and the equation in order to calculate hemofiltration clearance. The unbound fraction of a 4.0 g flucloxacillin dosage facilitates time above the minimum inhibitory concentration (T > MIC) of 60% only for strains up to a minimum inhibitory concentration (MIC) of 0.5 mg/l., Conclusion: Based on the data of this study, we conclude that intensive care patients with staphylococcal infections on CVVH should be treated with 4.0 g flucloxacillin every 8 h which was safe and well tolerated. Moreover, further studies with highly protein-bound drugs are recommended to check the classical 'hemodialysis' equation as the standard equation in calculating the CVVH clearance of highly protein-bound drugs., (Copyright 2003 S. Karger AG, Basel)

A new microgranulated formulation of amoxicillin trihydrate for in-feed medication was developed using a lipogelled matrix. Its relative bioavailability was compared with powdered drug in pigs and an assessment was made to determine whether therapeutic concentrations were achieved. Microgranules containing 10% (MICR10) and 30% (MICR30) amoxicillin and free amoxicillin trihydrate powder (reference, AMX) were administered at dosages of 50 mg of amoxicillin/kg b.w. using a three-way-crossover design. Amoxicillin analysis in serum was performed by a sensitive high performance liquid chromatography (HPLC) method with fluorometric detection, using an extraction procedure already described for edible tissues of fish and adapted and validated for pig serum. The oral bioavailability of both microgranulated formulations was higher than that of the reference formulation [relative bioavailability (F): 153.9 +/- 58.2% for MICR10; 126.2 +/- 70.5% for MICR30] and the area under the concentration-time curve (AUC) values of MICR10 and AMX formulations were significantly different (P < 0.05). Differences between the mean maximum concentration (Cmax), time of Cmax (tmax) and mean residence time (MRT) of the drug formulations were not significant. Microgranulated amoxicillin is suitable for in-feed administration to pigs and, because of its higher oral bioavailability compared with the powdered compound, it may be more effective for the treatment of susceptible infections.

The disposition of penicillin G in piglets is described after intramuscular or subcutaneous injection of depot preparations. The piglets were injected with 33,000 IU/kg or 100,000 IU/kg benzathine + procaine penicillin G intramuscularly or subcutaneously, or 100,000 IU/kg procaine penicillin G intramuscularly or subcutaneously. Intramuscular injection of benzathine + procaine penicillin resulted in higher maximum concentrations in plasma (Cmax) than did subcutaneous injection. The mean residence time (MRT) of penicillin G was longer when the drugs were injected subcutaneously rather than intramuscularly. The plasma concentration versus time profiles of the subcutaneous injections of benzathine + procaine penicillin revealed secondary peaks, possibly reflecting a certain degree of inflammation at the injection site.

A rapid, selective and sensitive HPLC assay has been developed for the routine analysis of amoxicillin in rat plasma, gastric juice aspirate and gastric tissue which is applicable to low concentrations of amoxicillin (<1 microg mL(-1)) or small sample volumes. Amoxicillin was converted, via an internal rearrangement, to form a fluorescent product which was subsequently recovered using liquid-liquid extraction. A Kromasil ODS 3 microm (150 x 3.2 mm I.D.) column was maintained at 40 degrees C and used with a mobile phase consisting of methanol-water (55:45, v/v). Fluorimetric detection was at an lambda(ex) of 365 nm and an lambda(em) of 445 nm. The limits of quantitation for amoxicillin were 0.1 microg mL(-1) for gastric juice aspirate (500 microL), 0.5 microg mL(-1) for plasma (50 microL) and 0.075 microg g(-1) for gastric tissue (250 mg). The method was linear up to at least 15 microg mL(-1) in gastric juice aspirate, up to 200 microg mL(-1) in plasma and up to 100 microg g(-1) in gastric tissue, with inter- and intra-day RSDs being less than 19%. The assay has been applied to the measurement of amoxicillin in rat plasma, gastric juice aspirate and gastric tissue for pharmacokinetic studies in individual rats.

The pharmacokinetics of amoxycillin was studied in nine male beagle dogs under healthy and febrile conditions. In Period 1, dogs received 20 mg/kg of an oral suspension of amoxycillin. Intravenous doses of saline, 2 and 20 microg/kg of endotoxin (LPS from Escherichia coli serotype) were administered to dogs (three per group) prior to administration of 20 mg/kg of amoxycillin in Period 2. Rectal temperature and behavioral changes were recorded and blood samples were collected over 12 h for pharmacokinetic analysis. Amoxycillin was assessed in plasma using liquid chromatography coupled with mass spectrometry. Plasma concentrations were analysed using a one-compartment model with lag-time for absorption using an iterative two-stage method. As compared with control groups, amoxycillin clearance decreased significantly with preliminary treatments of 2 microg/kg endotoxin (0.209 vs. 0.140 L/h kg, P < 0.05) and 20 microg/kg endotoxin (0.214 vs. 0.075 L/h kg, P < 0.05). As a result of this, the area under curve for the 2 and 20 microg/kg endotoxin groups increased significantly 100.4 vs. 149.4 microg h/mL (P < 0.05) and 99.2 vs. 277.7 microg h/mL (P < 0.05), respectively. Other drugs currently used for the treatment of fever and septic shock should be re-evaluated using a febrile animal model to avoid improper dose administration.

Methicillin-susceptible Staphylococcus aureus (MSSA) is the most common pathogen recovered from osteomyelitis patients. The current standard therapeutic method for acute phase osteomyelitis is parenteral antibiotic therapy. However, parenteral administration has negative aspects, such as secondary infection, patient inconvenience and high cost. The use of single oral antibiotic therapy may alleviate these problems. Therefore, the purpose of this study was to compare the effectiveness of standard once per day dosing of oral levofloxacin with a standard parenteral antibiotic regimen (nafcillin four times daily) for the treatment of experimental MSSA osteomyelitis in rabbits. Nearly all tibias from untreated infected controls (n = 27) revealed positive cultures (93%) for S. aureus, while the levofloxacin-treated group (n = 20) demonstrated significantly lower percentages of S. aureus infection (50%). The infected tibias of the nafcillin-treated group (n = 20) demonstrated significantly lower percentages (10%) of infected tibias than either the controls or the levofloxacin-treated groups (P < 0.05). The inferior efficacy of levofloxacin may have been due to the pharmacokinetic profile of this fluoroquinolone. The serum kinetics demonstrated that following single dose administration, levofloxacin was almost undetectable after 12 h. Studies in which levofloxacin is dosed every 12 h or given at increased doses in order to obtain bactericidal concentrations throughout the treatment regimen are needed.

Exercise produces changes of drug levels in plasma and increases the concentration of free fatty acids (FFAs), which may interfere with drug-protein binding. FFAs seem to play an antagonistic role to drugs since they have a strong binding capacity to serum albumin. The aim of this study was to evaluate the influence of the consecutive exercise-induced stress in ampicillin levels. Two groups of Wistar rats were used. Group A consisted of six subgroups that were subjected to cold swimming (4 degrees C) for 5, 10, 15, 20,25, 30 days respectively. Group B was the control group. The animals were injected im. with ampicillin (1 g/Kg/8h in 5 doses). Results showed that exercise enhanced stress parameters (FFAs, adrenal weight, Ht%) and led to an ampicillin increase in all experimental groups comparatively to controls.

Eighteen 1-week-old Holstein calves were randomly assigned to one of three groups: (a) sodium penicillin G administered intravenously, (b) sodium penicillin G administered orally, or (c) procaine penicillin G administered orally. All calves were dosed with penicillin G at 4.0 mg/kg BW. At 5 weeks of age, the calves were dosed again. Blood samples were taken serially for 24 h after both dosings. Plasma was assayed for penicillin G by high performance liquid chromatography (HPLC). For i.v. administration, the area under the concentration-time curve (AUC), 7456 and 5508 ng/mL h, and systemic clearance, 0.54 and 0.73 L/kg h, were significantly different (P < 0.05) at 1 and 5 weeks of age, respectively. There were no significant differences between orally administered sodium and procaine penicillin G within the same age groups. Following oral (p.o.) administration, there were significant differences (P < 0.01) at 1 and 5 weeks of age in the AUC, 760 and 409 ng/mL h, terminal half-life, 2.1 and 1.6 h, time of maximum concentration (TMAX), 3.0 and 2.3 h, and maximum plasma concentration (CMAX), 85 and 58 ng/mL, respectively. Bioavailability was 10.2 and 7.4% at 1 and 5 weeks, respectively.

Objective: The purpose of this study was to evaluate various oral antimicrobial agent levels in tooth extraction sites., Study Design: The concentration of dental alveolar blood in extraction wounds after the oral administration of talampicillin (500 mg), cefaclor (500 mg), cefteram pivoxil (200 mg), cefuroxime axetil (250 mg), cefdinir (200 mg), and ofloxacin (100 mg) was determined in 338 patients and was assessed on the basis of its antimicrobial activity against Streptococcus isolated in odontogenic infections., Results: The percentage of patients whose concentrations exceeded the minimum inhibitory concentration for 90% of Streptococcus was 62.5% to 100% for talampicillin at 30 to 360 minutes, 0% to 12.5% for cefaclor at 30 to 360 minutes, 18.2% to 100% for cefteram pivoxil at 30 to 480 minutes, 50% to 100% for cefuroxime axetil at 30 to 480 minutes, 0% to 50% for cefdinir at 16 to 290 minutes, and 0% to 40% for ofloxacin at 30 to 480 minutes., Conclusion: These results indicate that talampicillin, cefteram pivoxil, and cefuroxime axetil have minimum inhibitory concentration levels for 90% of Streptococcus in tooth sockets.

Objective: To compare the bioavailability of two amoxicillin oral suspension (250 mg/5 ml) formulations and two amoxicillin capsule (500 mg) formulations (Amoxicilina from Medley S/A Indústria Farmaceûtica, Brazil, as test formulations and Amoxil from SmithKline Beecham Laboratórios Ltda., Brazil, as reference formulations) in 48 volunteers of both sexes., Material and Methods: The study was conducted open with a randomized two-period crossover design and a one-week washout period. Plasma samples were obtained over a 12-hour interval. Amoxicillin concentrations were analyzed by combined reversed phase liquid chromatography and tandem mass spectrometry (LC-MS-MS) with positive ion electrospray ionization using the selected ion monitoring method. From the amoxicillin plasma concentration vs. time curves the following pharmacokinetic parameters were obtained: AUC(last), AUC(0-infinity) and Cmax., Results: Geometric mean of Amoxicilina/Amoxil 250 mg/5 ml individual percent ratio was 103.70% for AUC(last), 103.15% for AUC(0-infinity) and 106.79% for Cmax. The 90% confidence intervals were 97.82-109.94%, 97.40 to 109.24%, and 96.38-118.33%, respectively. Geometric mean of Amoxicilina/Amoxil 500 mg capsule individual percent ratio was 93.26% for AUC(last), 93.27% for AUC(0-infinity) and 90.74% for Cmax. The 90% confidence intervals were 85.0-102.33%, 85.12-102.31%, and 80.14-102.73%, respectively., Conclusion: Since the 90% CI for both Cmax, AUC(last) and AUC(0-inifnity) were within the 80-125% interval proposed by the Food and Drug Administration, it was concluded that Amoxicilina 250 mg/5 ml oral suspension and Amoxicilina 500 mg capsule were bioequivalent to Amoxil 250 mg/5 ml oral suspension and to Amoxil capsule 500 mg, respectively, with regard to both the rate and extent of absorption.

The fluorimetric property of the degrading products of piperacillin has been studied in detail. The studies on degrading pH, degrading time, detection alkalinity and other corresponding analytical parameters of acid degradation have been made. Then fluorometry of piperacillin was established by producing its stable fluorescent products. The detection limit for acid degradation analytical method is 2.34 ng/ml, the linear range is 7.80-4.0 x 10(2) ppb. The analytical sensitivity, precision and stability of degrading products of acid degradation are satisfactory, which has been used for the determination of the trace piperacillin in human serum and urine with satisfactory results.

Ticarcillin and clavulanic acid (potassium clavulanate) were administered to normal oestrous mares intravenously (i.v.) at a dose of 50 and 1.67 mg/kg for ticarcillin and clavulanate, respectively. In a crossover design, the same drugs were administered intrauterine (i.u.) at a dose of 12.4 and 0.4 mg/kg for ticarcillin and clavulanate, respectively. The i.u. dose was administered in 100 mL of saline solution. Endometrial tissue biopsies and plasma samples were collected after drug administration for the determination of ticarcillin and clavulanate concentrations by high-pressure liquid chromatography and pharmacokinetic calculations. After i.u. administration both drugs were poorly absorbed into the plasma. The ticarcillin half-life from tissue and plasma was short after i.v. administration. Although concentrations in tissue were higher after i.u. administration than i.v., concentrations of ticarcillin declined rapidly, which would necessitate frequent treatment in order to maintain drug concentrations above the minimum inhibitory concentrations (MIC) throughout the treatment period. Clavulanate concentrations in tissue were either low or persisted for only a short time after administration via either route. It appears that addition of clavulanate to the formulation for treatment of i.u. infections in mares is of questionable value based on these concentrations.

The MIC90 of glycylcycline (< or =0.06 mg/L) against 55 strains of Streptococcus pneumoniae was 100-fold lower than that of minocycline or tetracycline. In a mouse model of penicillin-resistant S. pneumoniae (PRSP) pneumonia, glycylcycline (10 mg/kg) decreased bacterial counts in the lungs from 10(6) cfu to <10(2) cfu, whereas no apparent reduction of bacterial numbers was observed with minocycline or penicillin G. Pharmacokinetic studies showed that the half-life and area under the curve of glycylcycline were superior to those of minocycline and penicillin G in the lungs. These results show a preferential distribution of glycylcycline in the lungs and potent in vivo bactericidal activity in PRSP pneumonia.

Objective: To determine pharmacokinetics and tissue distribution of amoxicillin in healthy and Salmonella Typhimurium-inoculated pigs., Animals: 12 healthy pigs and 12 S Typhimurium-inoculated pigs., Procedure: Concentration of amoxicillin in tissue was measured by use of high-performance liquid chromatography 4, 8, 12, and 24 hours after IM administration. Pharmacokinetic values of amoxicillin in plasma were assessed by use of a 1-compartment model with first-order absorption., Results: Inoculation caused diarrhea and increased rectal temperature and WBC count. Absorption half-life was shorter in inoculated pigs (0.26 hours) than in healthy pigs (0.71 hours), and inoculated pigs had longer elimination half-life. Distribution ratios in healthy pigs ranged from 0.31 to 0.56 and in inoculated pigs ranged from 0.14 to 0.48. Ratios for distribution to intestinal mucosa ranged from 0.34 to 1.16 in healthy pigs and from 0.22 to 0.36 in inoculated pigs., Conclusions and Clinical Relevance: Salmonella Typhimurium inoculation altered absorption of amoxicillin from the injection site and prolonged elimination half-life. However, distribution of amoxicillin to intestinal tract tissue was only affected to a minor degree.

Objective: To compare the pharmacokinetics of penicillin G and procaine in racehorses following i.m. administration of penicillin G procaine (PGP) with pharmacokinetics following i.m. administration of penicillin G potassium and procaine hydrochloride (PH)., Animals: 6 healthy adult mares., Procedure: Horses were treated with PGP (22,000 units of penicillin G/kg of body weight, i.m.) and with penicillin G potassium (22,000 U/kg, i.m.) and PH (1.55 mg/kg, i.m.). A minimum of 3 weeks was allowed to elapse between drug treatments. Plasma and urine penicillin G and procaine concentrations were measured by use of high-pressure liquid chromatography., Results: Median elimination phase half-lives of penicillin G were 24.7 and 12.9 hours, respectively, after administration of PGP and penicillin G potassium. Plasma penicillin G concentration 24 hours after administration of penicillin G potassium and PH was not significantly different from concentration 24 hours after administration of PGP. Median elimination phase half-life of procaine following administration of PGP (15.6 hours) was significantly longer than value obtained after administration of penicillin G potassium and PH (1 hour)., Conclusions and Clinical Relevance: Results suggest that i.m. administration of penicillin G potassium will result in plasma penicillin G concentrations for 24 hours after drug administration comparable to those obtained with administration of PGP Clearance of procaine from plasma following administration of penicillin G potassium and PH was rapid, compared with clearance following administration of PGP.

We evaluated, by time-kill studies, the pharmacodynamics of amoxicillin/sulbactam (AMX/SUL, 875 mg/125 mg), a novel oral combination, against the major respiratory pathogens in 12 volunteers receiving a single dose. The sera corresponding to 50% of a 12-h dosing interval displayed either bactericidal or inhibitory activity against both a penicillin-susceptible and a penicillin-intermediate Streptococcus pneumoniae strain (penicillin MIC of 0.03 and 0.25 microg/ml, respectively), as well as against a beta-lactamase-positive Moraxella catarrhalis and a beta-lactamase-negative Haemophilus influenzae strain. Both the peak samples and those corresponding to 4 h after dose (i.e. 33% of a 12-h dosing interval) proved active against both a penicillin-resistant S. pneumoniae (MIC, 2 microg/ml) and a beta-lactamase-positive H. influenzae strain. The AMX-SUL formulation evaluated in this study showed pharmacodynamic features that support clinical trials to assess its efficacy in the treatment of lower respiratory tract infections with a 12-h dosing interval regimen.

The aim of this study was to determine the interaction between omeprazole and amoxicillin, being common agents used in the eradication regimen for H. pylori infection. Amoxicillin concentrations in gastric mucosa and serum were quantitatively analysed in 12 patients with non-ulcer dyspepsia following the administration of one week duration of placebo as group I and omeprazole as group II. The study was a blind, cross-over design with a one week wash out period between the two treatment groups. Six antral gastric mucosa were biopsied 90 minutes after oral administration of amoxicillin. Blood samples were collected before and after administration at intervals up to 6 hours. All samples were analysed for amoxicillin concentration using the HPLC technique. Highly intersubject variations of amoxicillin concentrations were observed. The concentration of amoxicillin in gastric mucosa ranged from 0.00-1.74 and 0.00-1.25 micrograms/mg for group I and group II, respectively, with the mean concentration of 0.25 +/- 0.48 microgram/mg for group I and 0.28 +/- 0.40 microgram/mg for group II. The difference was not statistically significant (p = 0.89). Pharmacokinetic parameters of amoxicillin in serum following regimen I and regimen II were not significantly different (p > 0.05). The mean Cmax values were 14.62 +/- 5.39 and 12.65 +/- 4.76 micrograms/ml, the Tmax were 2.3 +/- 1.0 and 2.0 +/- 0.9 hour and the AUC0-6 were 40.79 +/- 13.26 and 38.75 +/- 15.04 micrograms/ml.h in the group I and group II, respectively. From these results, we concluded that omeprazole has no effect on gastric mucosa level nor serum levels of amoxicillin. The therapeutic efficacy of using these two agents in the eradication regimen of H. pylori may be related to other factors rather than pharmacokinetic interaction.

Comparative randomized opened pharmacokinetic evaluation of benzathine benzylpenicillin in three dosage forms was performed. Benzathine benzylpenicillin was used as extencilline (2.4 million U or 1.2 million U, "Rhône-Poulenc Rorer", France) and as bicillin-5 (1.5 million U, "Synthesis" Russia). 33 patients were included in investigation (23 women and 10 men aged 16-60 years). 25 persons had verified rheumatism without blood circulation failure signs, 4--had chronic tonsillitis and 4 were healthy volunteers. Benzylpenicillin concentration was estimated by microbiology test in blood samples taken at 1, 3, 24 hours and 7, 14 and 21 days after intramuscular drug injection. After 2.4 million U extencilline injection (12 patients) its concentration, was at the inhibition level for beta-hemolytic streptococcus group A (25 ng/ml) for 3 weeks-period in 83.3 per cent of patients. After 1.2 million U extencilline injection (10 patients) or 1.5 million U bicillin-5 injection (12 patients) the above mentioned concentration was achieved on the 21st day in 30 and 0 per cent of patients respectively. Thus the treatment with benzathine benzylpenicillin at the 1.2 million U dose in the form of extencilline or bicillin-5 doesn't provide adequate antistreptococcal concentration in blood in prolonged period and is not suitable for correct rheumatism prophylaxis in adult patients.

A fluorescence assay based on the use of biological reducing agents as catalysts rather than heavy metal ions has been developed for estimation of ampicillin concentrations. The assay is based on the conversion of ampicillin to its penicilloate, by treatment with sodium hydroxide, then neutralization, dilution with 0.5 M acetate buffer at pH4 and heating for 30 min at 100 degrees C in the presence of ascorbic acid (0.5 mg) and EDTA (50 microM). Reduced glutathione, cysteine and N-acetylcysteine also catalysed the development of fluorescence. A practical sensitivity range of 0.5-50 microM ampicillin was used. The assay was used to estimate ampicillin in some biological solutions to which the antibiotic has been added. Milk, blood serum, trypticase soy broth and nutrient broth containing 25 microM antibiotic assayed at 18.5, 21.7, 16.5 and 14.7 microM, respectively, with standard deviations between 1.2 and 0.7%. The low results were attributed to binding of some ampicillin by proteins or peptides which were removed by pretreatment. Urine containing 5 mM ampicillin assayed at 4.97 mM with a standard deviation of 3%. A modification of the procedure was used to measure beta-lactamase activity against ampicillin in several organisms in a fixed time assay. Kinetic parameters of a commercial beta-lactamase preparation from Bacillus cereus could also be determined by an additional modification. In both instances a correction was required for the intrinsic fluorescence of ampicillin remaining in the solution. The preparation examined had a Michaelis constant (Km) of 0.32 mM, a maximum velocity (Vmax) of 5398 micromol ampicillin hydrolysed mg(-1) min(-1), an apparent catalytic constant (Kcat, turnover number) of 20,220 s(-1) and a Kcat/Km ratio of 0.63 x 10(7) M(-1) s(-1). The major advantage of using this assay technique is that toxic metals are not used in the development of fluorescence so it is more environmentally acceptable. The technique is useful for examining beta-lactamase activity against ampicillin and might be useful for pharmaceutical products-for determining available therapeutic levels and for monitoring the activity of penicillin acylase against the penicilloate of ampicillin.

The borreliacidal-antibody test has been used for the serological detection and confirmation of Lyme borreliosis. However, the presence of antimicrobial agents in serum can confound the accurate detection of borreliacidal antibodies. In this study, we developed a Bacillus subtilis agar diffusion bioassay to detect small concentrations of antimicrobial agents in serum. We also used XAD-16, a nonionic polymeric resin, to adsorb and remove high concentrations of amoxicillin, cefotaxime, ceftriaxone, cefuroxime, doxycycline, and erythromycin without significantly affecting even small concentrations of immunoglobulin M (IgM) or IgG borreliacidal antibodies. High concentrations of penicillin could also be removed by adding 1 U of penicillinase without significantly influencing the levels of borreliacidal antibodies. These simple procedures greatly enhance the clinical utility of the borreliacidal-antibody test.

In Morocco, neurosyphilis is a serious public health problem. In the neurology service at the specialist hospital in Rabat, two drug treatments were used. Treatment A consisted of infusion over a period of 4 h of 20 MUI of penicillin G per day for 3 weeks. Treatment B consisted of infusion over a period of 6 h of 30 MUI of penicillin G per day for 10 days. Each treatment was tested on a group of eight neurosyphilitic patients as first-line treatment. On the first day of treatment, both blood and CSF pharmacokinetics were sampled for each patient. Blood and CSF were taken within 24 h. Penicillin G concentrations were determined by a microbiological method. The results obtained showed that perfusions of either 20 MUI or 30 MUI of penicillin allowed the achievement of high serum concentrations. These increased progressively until reaching their maximum at T4 h for treatment A (from 92.33 to 106.38 micrograms/ml). For treatment B, maximal concentration is obtained at T6 h (from 108 to 141.52 micrograms/ml). Penicillin concentrations decreased immediately after stopping the perfusion. At CSF levels, penicillin G concentrations were identical to serum concentrations. However, one difference was observed: a one-hour difference between the serum and CSF peaks. The CSF peak was achieved at T5 h for treatment A (0.063 to 2.25 micrograms/ml) and at T7 h for treatment B (0.92 to 2.94 micrograms/ml). The concentrations obtained were largely superior to the CMI of Treponema pallidum for both treatment A and treatment B, at 47 times and 82 times higher respectively. The recovery time of the patients was 14 h for treatment A and 24 h for B treatment. These results have shown that therapeutic method B was more efficient than A. Moreover, the evolution of penicillin G's diffusion in the CSF during treatment, of cell counts of protein level, of the VDRL test and of the gamma-globulin rate was studied.

The delivery of antibiotics into Helicobacter pylori-infected human stomachs is still poorly understood. Human embryonic gastric xenografts in nude mice have recently been proposed as a new model for the study of H. pylori infection. Using this model, we compared the penetration of amoxicillin, after intraperitoneal administration of a dose of 20 mg/kg of body weight, into the gastric mucosae of infected and uninfected xenografts. The concentrations of this drug in serum and superficial gastric mucosae were determined at 20 min and 1 and 3 h after injection. Ten mice with H. pylori-infected grafts (n = 5) or uninfected grafts (n = 5) were studied. Mucosal samples were obtained by cryomicrotomy. The concentrations in serum were similar to those obtained in the serum of humans after oral administration of 1 g of amoxicillin. The mean area under the tissue concentration-versus-time curve from 0 to 3 h obtained for mice with infected grafts was significantly higher than that obtained for the animals with uninfected grafts (P = 0.01). These results suggest that the penetration of amoxicillin into the superficial gastric mucosa may be substantially increased in the case of H. pylori infection. Thus, human xenografts in nude mice represent a new, well-standardized model for investigation of systemic delivery of drugs into H. pylori-infected gastric mucosa.

In order to explore the bactericidal activity of concentrations similar to the peak serum concentrations obtained after a single i.v. dose of 2,000/200 mg co-amoxiclav and 500 mg vancomycin, killing curves with co-amoxiclav (69/10 microg/ml), amoxicillin (69 microg/ml), clavulanic acid (10 microg/ml), and vancomycin (15 microg/ml) were performed against two isogenic (ss-lactamase positive and negative) methicillin-resistant Staphylococcus aureus strains in cation-supplemented Mueller-Hinton broth with 2% NaCl incubated at 35 degrees C. Colony counts were performed at 0, 1, 2, 3 and 4 hours in Mueller- Hinton plates supplemented with 4% NaCl and 25 microg/ml oxacillin to measure the resistant population. Similar initial inocula reductions were obtained for amoxicillin-clavulanic acid and vancomycin for both strains, and significant differences were found in comparison to the control. Clavulanic acid decreased the growth rate of the ss-lactamase negative strain when compared to control curves. The penicillin-binding protein 2a affinity of old ss-lactams in conjunction with clavulanic acid overcoming ss-lactamase resistance may explain these results.

The effects of anaesthesia on intestinal drug absorption and hepatic first-pass metabolism in rats were investigated by observing the difference in the drug concentration between portal and systemic bloods. Oxacillin and pentobarbital were selected as a model drug and as an anaesthetic, respectively. Rats were divided into a conscious control group and an anaesthetized group. All rats were cannulated simultaneously in the portal vein and in the femoral artery, and oxacillin was orally administered after its intra-arterial injection (double dosing). For the anaesthetized group, pentobarbital was intrasubcutaneously administered twice, first before intra-arterial injection and again before oral administration of oxacillin. The arterial blood alone was sampled from the cannula in the femoral artery before oral administration, whereas the arterial and portal bloods were simultaneously sampled from both cannulated sites after oral administration. Oxacillin concentrations in plasma were assayed by HPLC. The anaesthesia increased the absolute bioavailability (F), the mean absorption time (MAT) and the hepatic recovery ratio (F(H)), but caused little change in the local absorption ratio into the portal system (Fa) and the total clearance (CL). The hepatic clearance (CL(H)) was significantly decreased, resulting in an apparent small change in CL-CL(H) which is considered to be renal clearance. By this method, it was shown directly that an increase in F due to pentobarbital anaesthesia was attributable to the significant increase in F(H). It is expected that the method is useful not only to evaluate the effect of anaesthesia on the first-pass effect, but also to assess the effect of co-administration of drugs on first-pass metabolism.

A high-performance liquid chromatography column-switching system for the automated determination of amoxicillin in human serum was developed as a more efficient alternative for the already existing systems with off-line sample pretreatment. The column-switching system consists of a semipermeable surface (SPS) column and an analytical reversed-phase (RP) C18 column. After centrifuging, pure serum samples were injected into the column-switching system. Clean-up, with regard to removal of proteins, was performed on the SPS column. The fraction containing amoxicillin was concentrated on the analytical RP-C18 column. Finally, chromatography and detection were performed with the RP-C18 column using UV detection at 234 nm. The total analysis time was 15 min. The method has proven to be reliable and to be more time- and resource-efficient compared to previously used methods with off-line sample clean-up. It is now used in bioavailability studies for the development of new amoxicillin formulations.

Fusidic acid and cloxacillin were studied in patients who underwent joint aspiration for noninfectious disorders. Nine patients were given oral 500 mg fusidic acid tid for 72 h, the last dose being given 4, 8 or 12 h before the joint aspiration. Cloxacillin was administered in a single 2 g iv dose to 9 patients, 0.5, 4 or 8 h before the aspiration. Bactericidal activity was determined against five isolates each of methicillin-susceptible and methicillin-resistant Staphylococcus aureus. Satisfactory activity (> or = 1:3) was detected in the serum in patients who received fusidic acid, while in the synovial fluids titres reflected borderline effectiveness (c. 1:2). Despite drug concentrations and excellent MICs, fusidic acid demonstrated markedly lower inhibitory and bactericidal activity against S. aureus than did cloxacillin.

Several lower respiratory tract infection (LRTI) trials have documented a correlation between clinical response and area under the inhibitory curve (24 h AUC/MIC; AUIC). The AUIC values in these studies were based on measured MICs and measured serum concentrations. This study evaluates AUIC estimates made using population pharmacokinetic parameters, and MICs from an automated microbiological susceptibility testing system. A computer database review over 2 years yielded 81 patients at Millard Fillmore Hospital with a culture-documented gram-negative LRTI who had been treated with piperacillin and an aminoglycoside, ceftazidime, ciprofloxacin or imipenem. Their AUIC values were estimated using renal function, drug dosages and MIC values. Outcome groups (clinical and microbiological cures and failures) were related to the AUIC values using Kruskal-Wallis ANOVA, linear regression and classification and regression tree (CART) analysis. A significant breakpoint for clinical cures was an AUIC value at least 72 SIT(-1) x 24 h (inverse serum inhibitory titre integrated over time). All antibiotics performed significantly better above this value than below it. Clinical cure was well described by a Hill-type equation. Within the piperacillin/aminoglycoside regimen, most of the activity came from the piperacillin, which had a higher overall AUIC value than the aminoglycoside. AUIC estimations based upon MIC values derived from the automated susceptibility testing method differed from NCCLS breakpoint data and from tube dilution derived values in this hospital by as much as three tube dilutions. These automated methods probably overestimated the MIC values of extremely susceptible organisms. The lack of precise MIC estimates in automated clinical microbiology methods impairs the use of AUIC to prospectively optimize microbiological outcome. Even ignoring this limitation and using the values as they are reported, the results of this analysis suggest that AUIC targets between 72 and 275 SIT(-1) x 24 h are useful in predicting clinical outcome.

A reversed-HPLC method was established to determinate penicillins in whole blood. Thiamphenicol as internal standard was added to 0.5 ml blood. Proteins in blood were precipitated with acetonitrile, then the separate supernatant was directly injected onto the chromatography column. The range of five penicillins' linearities was 0.9918 to 0.9996, their range of relative recovery was 91.75% to 107.33%, their CV was 3.56% to 9.85%. Effects of different storage temperatures on the stability of analytes and interference of other antibiotics were also studied.

Since the efficacy of beta-lactams against pathogens such as methicillin-susceptible Staphylococcus aureus (MSSA) is related to the time for which serum drug concentrations exceed the MIC for the pathogen, administration of anti-staphylococcal beta-lactams by continuous infusion may provide a more suitable means of drug delivery than intermittent dosing. To assess the clinical efficacy of continuous-infusion therapy, we reviewed the outcomes for 20 consecutive patients with proven serious MSSA sepsis (three with endocarditis, ten osteomyelitis, one endocarditis plus osteomyelitis and six deep abscess) treated with continuous-infusion flucloxacillin (8-12 g/day). Patients initially receiving routine intermittent-dose flucloxacillin therapy were changed to continuous-infusion flucloxacillin (mean duration 29 days; range 4-60 days) for completion of their treatment course. In the majority of cases this was given at home. Serum flucloxacillin concentrations during continuous-infusion flucloxacillin 12 g/day were 11.5->40 mg/L (ten patients) and those during continuous-infusion flucloxacillin 8 g/day were 8->40 mg/L (five patients), these concentrations being well above the expected MIC of flucloxacillin for MSSA. Continuous-infusion flucloxacillin was well tolerated by most patients, and 14/17 patients (82%) who completed their course of continuous-infusion flucloxacillin were judged clinically and microbiologically cured at long-term follow-up (mean 67 weeks; range 4-152 weeks). These preliminary data suggest that, following initial intermittent-dose flucloxacillin therapy, continuous-infusion flucloxacillin is an effective treatment option for serious MSSA sepsis, and forms a feasible and possibly preferable alternative to glycopeptides when considering home-based parenteral therapy for these infections. Further studies are needed to identify whether continuous-infusion flucloxacillin can entirely replace intermittent-dose therapy for such infections.