Impact of milk yield on pharmacokinetics of six intramammary drugs - a population approach.

The aim of the research was an examination of potential impact of milk yield on the intercompartmental clearance - distribution clearance as well as determination of the variability of obtained pharmacokinetic parameters by the population approach using a two-compartmental structural model. Blood perfusion has a considerable impact on physiology of the udder and kinetics of drugs that are distributed in this organ. The research was performed on healthy Holstein- Friesian and Polish Black-White cows at the age of 4-10 years. Determination of antibiotics (ampicillin, amoxicillin, cefoperazone, penicillin G prokaine, cloxacillin, cefacetril) concentration was carried out after their every intramammary administration to one quarter of the udder. A population pharmacokinetic model was created to fit milk concentration data. General milk yield of a single cow was used as a variable. A population analysis was conducted using non-linear mixed-effect modeling. The impact of milk productivity was set solely by reference to intercompartmental clearance only in case of penicillin G, cloxacillin and ampicillin. It, has been found that milk yield, depending on a drug, influenced the distribution clearance of the drug to varying degrees. It means indirectly that increased perfusion of the udder has a different impact on drug distribution from the udder to the bloodstream.

Plasma disposition of cefoperazone after single intravenous and intramuscular administrations in camels (Camelus dromedarius).

The plasma disposition of cefoperazone was investigated after intravenous (IV) and intramuscular (IM) administrations of 20 mg/kg as a single dose in six camels (Camelus dromedarius) in a crossover design. Blood plasma samples were analysed by high-performance liquid chromatography (HPLC). After IV administration, elimination half-life (t1/2ß), volume of distribution at steady state (Vdss), total body clearance (Cltot) and mean residence time (MRT) of cefoperazone were 1.95 h, 0.38 L/kg, 0.17 L/h/kg and 2.16 h, respectively. After IM administration of cefoperazone, peak plasma concentration (Cmax) was 21.95 µg/mL and it was obtained at (tmax) 1.23 h. Absorption half-life (t1/2ab), elimination half-life and mean absorption time were 0.45 h, 2.84 h and 2.07 h, respectively. The bioavailability of cefoperazone was 89.42%. The lack of local reaction or any other adverse effects and the very good bioavailability following IM administration indicate that cefoperazone might be a promising alternative treatment for a variety of infectious diseases in camels.

Determination of cefoperazone and sulbactam in serum by HPLC-MS/MS: An adapted method for therapeutic drug monitoring in children.

A rapid, accurate and specific high-performance liquid chromatography-tandem mass spectrometry method has been validated for the simultaneous determination of cefoperazone and sulbactam in a small volume sample for children. A Shim-pack XR-ODS C18 column with gradient elution of water (0.1% formic acid) and acetonitrile (0.1% formic acid) solution was used for separation at a flow rate of 0.3 mL/min. The calibration curves of two analytes in serum showed excellent linearity over the concentration ranges of 0.03-10 µg/mL for cefoperazone, and 0.01-3 µg/mL for sulbactam, respectively. This method involves simple sample preparation steps and was validated according to standard US Food and Drug Administration and European Medicines Agency guidelines in terms of selectivity, linearity, detection limits, matrix effects, accuracy, precision, recovery and stability. This assay can be easily implemented in clinical practice to determine concentrations of cefoperazone and sulbactam in children.

Withdrawal of cefoperazone with milk after intramammary administration in dairy cows - prospective and retrospective analysis.

The aim of the study was to carry out retrospective and prospective comparative analyses of the pharmacokinetics of CEF after single intramammary (IMM) administration in cows. The prospective study (study A) was conducted on 9 dairy cows of the Polish Black-White race with clinical mastitis during the lactation period. Milk samples were collected at 2, 4, 6, 8, 10, 24, 36, 48, 72 and 84 h after single IMM administration of 250 mg of CEF to one quarter. Drug concentrations in milk samples were determined by HPLC-MS/MS technique and the results of the pharmacokinetic analysis were compared to those obtained in previous studies based on the microbiological (study B) and HPLC-UV methods (study C and D). Pharmacokinetic parameters were calculated based on adapted two-compartment model of drug distribution. One of the findings of the comparison of the analysed investigations is that the CEF kinetics determined with the microbiological method is consistent with the results obtained by the authors of this paper. Both studies yielded similar results of the key pharmacokinetic parameters related to the level of the drug distribution to tissues and elimination half-life. In the pharmacodynamic analysis, the observations in all four studies were entirely consistent and have shown lower values of T>MIC90 in healthy animals and significantly higher values in infected dairy cows. The comparison of studies A, B, C, and D revealed that the time of complete CEF wash-out of 90.90% varied and amounted to 5.7, 8.0, 2.2, and 2.2 days after administration of the drug, respectively. It was confirmed that not only the type of the analytical method but also correct sampling have a significant impact on determination of the correct value of the drug half-life after IMM administration. The comparative analysis of studies in which the milk yield was high and low allows a conclusion that this parameter in the case of CEF has no significant effect on T>MIC90.

Pharmacokinetics of cefoperazone/sulbactam in critically ill patients receiving continuous venovenous hemofiltration.

PURPOSE: Cefoperazone/sulbactam (CFP/SUL) is a ß-lactam/ß-lactamase inhibitor combination with little data available for the development of effective dosing guidelines during continuous renal replacement therapy. This study aimed to investigate the pharmacokinetics (PK) of cefoperazone/sulbactam in critically ill patients on continuous venovenous hemofiltration (CVVH). METHODS: A prospective, single-center, and open-label study was conducted. Critically ill patients receiving CVVH with 3 g cefoperazone/sulbactam (2.0/1.0 g) intravenously every 8 h were recruited. Serial blood and ultrafiltrate samples were paired collected for initial dose (occasion 1) and steady state (occasion 2). PK was assessed by non-compartmental analysis, and pharmacodynamics (PD) was evaluated by the percent of time for which drug concentrations exceed the minimum inhibitory concentration (%T >MIC). RESULTS: Total fourteen patients were enrolled. Volume of distribution at steady state (V ss) of cefoperazone and sulbactam for initial doses (20.8 ± and 28.4 L, respectively) increased significantly compared with those in healthy volunteers (P = 0.009 for CFP, P = 0.030 for SUL). Both cefoperazone and sulbactam showed significantly lower total clearance (CLt) (46.2 and 117.6 mL/min, respectively) compared with healthy volunteers (P = 0.000 for CFP, P = 0.017 for SUL). There is no significant difference in PK between occasion 1 and occasion 2 (P > 0.05). For occasion 1, mean CVVH clearance accounted for 34.3 and 33.9 % for CLt of cefoperazone and sulbactam, respectively. The minimum PD target of 60%T >MIC was achieved in seven of eight patients. For occasion 2, eight of nine patients achieved cefoperazone concentrations that were above the MIC for the entire dosing interval. CONCLUSIONS: PK of cefoperazone/sulbactam was altered in critically ill patients undergoing CVVH. Therapeutic drug monitoring would be recommended to individualize the dose regimen.

[Experimental study on concentrations and pharmacokinetics of antibiotics in bile and evaluation of their microbicidal potential].

OBJECTIVE: To study the concentrations and pharmacokinetics of 6 different kinds of antibiotics in rabbit bile, and evaluate their microbicidal potential. METHODS: Thirty-six health rabbits were randomly divided into 6 groups, and each group was 6 rabbits. After anaesthesia, the common bile duct of rabbit was isolated and cumulated with a silicone tube. The rabbits were administered intravenously with the equal-effect dose of antibiotics. Bile (1.5 ml) was collected at different time points after administration, and the concentration of antibiotics of bile was assayed by high performance liquid chromatography. The bile drug concentration-time data were processed by software to figure out the pharmacokinetic parameters such as maximum concentration (C(max)), peak time (T(max)), half-life time (T(1/2)), clearance (CL) and apparent volume of distribution (VD). The bile antibiotics concentration contrasted to the minimum inhibitory concentration (MIC), and attained the bactericidal index (C(max)/MIC) and the time when the drug concentration exceeded the MIC (T(>MIC)). RESULTS: The C(max) and T1/2 of each antibiotic were as the followings: piperacillin (7 950 ± 3 023) mg/L and (1.97 ± 1.23) h, ceftriaxone (1 104 ± 248) mg/L and (3.14 ± 0.57) h, cefoperazone (5 215 ± 2 225) mg/L and (0.89 ± 0.13) h, meropenem (31.97 ± 12.44) mg/L and (0.36 ± 0.11) h, levofloxacin (66.3 ± 36.9) mg/L and (3.32 ± 2.57) h, metronidazole (28.2 ± 10.2) mg/L and (0.81 ± 0.33) h, respectively. Piperacillin/tazobactam and cefoperazone/sulbactam had the largest bactericidal index and the longest T(>MIC), and their bactericidal indexes were (62.1 ± 23.6) - (993.8 ± 377.9) and (164.8 ± 69.0) - (659.3 ± 275.9), their T(>MIC) were (6.00 ± 2.53) - (8.00 ± 0.00) h and (6.33 ± 1.97) - (8.00 ± 0.00) h. The bactericidal index and T(>MIC) of levofloxacin were the smallest, which were (2.1 ± 1.2) - (8.3 ± 4.6) and (0.54 ± 0.25) - (2.67 ± 1.03) h . Ceftriaxone and meropenem were as the medium, and their bactericidal indexes and T(>MIC) were (4.3 ± 1.0) - (69.2 ± 15.5) , (1.42 ± 0.65) - (8.00 ± 0.00) h and (2.0 ± 0.8) - (1 031.3 ± 401.4) , (0.29 ± 0.10) - (1.83 ± 0.26) h. The bactericidal index of metronidazole to anaerobic ranged from 7.4 to 294.9, and the T(>MIC) ranged from 1.88 to 5.00 h. CONCLUSIONS: The bile concentrations of six antibiotics all exceed their effective bactericidal concentrations. The concentration-time curves of piperacillin, cefoperazone, meropenem and metronidazole conformed to one-compartment model, and ceftriaxone and levofloxacin are conformed to two-compartment model. Piperacillin/tazobactam and cefoperazone/sulbactam have the largest bactericidal index and the longest T(>MIC), so they can be chosen as the first choice for the therapy of hepatobiliary infection.For the anaerobic, the microbicidal potential of metronidazole is high.

Liquid chromatography/tandem mass spectrometry assay for the simultaneous determination of cefoperazone and sulbactam in plasma and its application to a pharmacokinetic study.

A rapid and highly sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) method for simultaneous determination of cefoperazone sodium and sulbactam sodium in human plasma was developed. The analytes and internal standard (IS), cefuroxime sodium, were extracted from human plasma via liquid-liquid extraction with ethyl acetate and separated on a Waters Xterra C18 column within 3.5 min. Quantitation was performed on a triple quadrupole mass spectrometer employing electrospray ionization technique, operating in selected reaction monitoring (SRM) and negative ion mode. The precursor to product ion transitions monitored for cefoperazone, sulbactam and IS were m/z 644.1→528.0, 232.1→140.0, and 423.0→362.0, respectively. The assay was validated in the linear range of 0.1-20 µg/mL for cefoperazone and 0.02-4 µg/mL for sulbactam. The intra- and inter-day precisions (CV%) were within 8.39% for each analyte. The recoveries were greater than 87.3% for cefoperazone and 87.2% for sulbactam. Each analyte was found to be stable during all sample storage, preparation and analytical procedures. The method was successfully applied in a pharmacokinetic study of Sulperazon injection in six hospital-acquired pneumonia (HAP) patients.

Cefoperazone sodium preparation behavior after intramammary administration in healthy and infected cows.

Selection of the antimicrobial agent and maintenance of adequate drug concentrations at the site of infection are the most relevant problems in mastitis antibiotic therapy. Intramammary drug efficacy can be maximized by keeping drug concentrations at the site of infection above the minimum inhibitory concentration (MIC) as long as possible; the most important pharmacokinetic and pharmacodynamic (PK/PD) measure for efficacy evaluation is time during which drug concentrations exceed the MIC (t>MIC). To evaluate this measure, the PK profile of cefoperazone (CFP) after single intramammary administration in healthy and subclinical infected Staphylococcus aureus cows and the MIC of Staph. aureus field strains were assessed. In addition, the degree of drug passage from udder to bloodstream was investigated by measuring systemic drug absorption in healthy and infected animals. Cefoperazone concentrations were quantified by HPLC in quarter milk samples and blood serum samples. Systemic drug absorption was negligible in healthy animals (0.020+/-0.006 microg/mL serum at 4 h), whereas it was higher in infected animals (0.102+/-0.079 microg/mL at 4h and 0.025 microg/mL at 24 h), probably due to the damage of epithelial cell junctions caused by subclinical infections. The MIC90 value for CFP in Staph. aureus field strains (n=24) was 0.64 microg/mL. The PK/PD evaluation, determined by t>MIC, showed a longer persistence of CFP in infected quarters than in healthy ones (mean residence time was 8.37+/-1.51 vs. 11.42+/-5.74 h in September and 2.07+/-0.43 vs. 3.31+/-0.91 h in October), with a t>MIC of 45+/-6 h for infected quarters versus 38+/-5 h for healthy quarters different only in October. This could mean a prolonged time in which microorganisms are exposed to drug activity and thus, a greater efficacy of the drug.

Maternal and fetal blood levels of moxifloxacin, levofloxacin, cefepime and cefoperazone.

Wide-spectrum quinolones such as moxifloxacin and levofloxacin as well as high-order cephalosporins such as cefoperazone and cefepime have increased antimicrobial activity. However, little is known about their distribution in fetal blood. Therefore, the aim of this study was to measure and compare maternal and fetal blood levels of these agents. For the measurement of blood levels, 9 pregnant women received cefepime hydrochloride, 10 received cefoperazone, 10 received moxifloxacin and 12 received levofloxacin intravenously. Maternal and umbilical cord blood samples were drawn during delivery. Antibiotic levels were analysed by high-performance liquid chromatography. Mean transplacental passage rates of moxifloxacin, levofloxacin, cefepime and cefoperazone were 74.84%, 66.53%, 23.21% and 12.68%, respectively, and mean transfetal passage rates were 90.78%, 84.22%, 79.17% and 79.78%, respectively. The transplacental passage rate for either quinolone was significantly higher than that of either cephalosporin, and the transplacental passage rate of cefoperazone was lower than that of cefepime. In conclusion, both quinolones have high transplacental passage rates. Cefepime and cefoperazone have a lower transplacental passage rate and thus may be used as prophylaxis in situations where transplacental passage is undesirable.

Sulbactam-containing beta-lactamase inhibitor combinations.

Sulbactam irreversibly inhibits the hydrolytic activity of beta-lactamases. This compound is commercially available in combination with either ampicillin or cefoperazone. In each instance, the activity of the partner antibiotic against beta-lactamase-producing bacteria is restored. One of the particular advantages of using sulbactam-containing combinations is that sulbactam itself has inherent activity against some Acinetobacter baumannii. Sulbactam combinations have not demonstrated strong selective pressures for extended-spectrum beta-lactamase-producing Enterobacteriaceae and vancomycin-resistant enterococci. In contrast to clavulanate, sulbactam does not induce class I (Ampc) chromosomal beta-lactamases in Enterobacteriaceae.

Bioequivalence study of the two 1.5 g cefoperazone and sulbactam IM injections in Thai healthy male volunteers.

OBJECTIVE: To perform a bioequivalence study of the two 1.5 g cefoperazone (1.0 g) and sulbactam (0.5 g) between Cefper and Sulperazon injections. MATERIAL AND METHOD: The present study was performed in 24 Thai healthy male volunteers who were intramuscularly injected a single dose of 1.5 g cefoperazone and sulbactam. A single dose, two periods, two sequences, double blind randomized crossover with a one-week washout period was used. Blood samples were collected before and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours after intramuscular injection and determined for cefoperazone and sulbactam plasma concentration by validated HPLC-UV methods. The pharmacokinetic parameters were analyzed by noncompartmental analysis and the ANOVA was carried out. RESULTS: Tax of both cefoperazone and sulbactam for volunteers who were injected with either Cefper or Sulperazon injection were not significantly different (p > 0.05). The 90% confidence intervals of the log of ratio of either C(max) or AUC(last) or AUC(inf) of both cefoperazone and sulbactam between 1.5 g Cefper and Sulperazon injections were within the bioequivalence range of 0.80-1.25. CONCLUSION: The 1.5 g cefoperazone and sulbactam injection of Cefper and Sulperazone used in the present study are bioequivalent.

Quantitative determination of unbound cefoperazone in rat bile using microdialysis and liquid chromatography.

Cefoperazone is a third generation cephalosporin antibiotic with a broad spectrum against gram-positive and gram-negative bacteria. It is clinically effective in the treatment of the biliary tract infections. In the present study, we utilized microdialysis sampling technique with shunt linear probe for continuous monitoring levels of cefoperazone from rat biliary ducts. The effects of berberine (a potential P-glycoprotein enhancer) pretreatment were also evaluated. Analysis of cefoperazone in the dialysates was achieved using a reversed phase RP-18 column (250 mm x 4.6 mm i.d.; particle size 5 microm) maintained at ambient temperature. The mobile phase comprised 100 mM monosodium phosphate (pH 5.5)-methanol (70:30, v/v), and the flow rate of the mobile phase was 1 ml/min. The UV detector wavelength was set at 254 nm. The area under the concentration-time curve and elimination half-life of cefoperazone were about 242.3+/-13.4 min mg/ml and 64.1+/-28.2 min, respectively. No significant effect was showed on the pharmacokinetics of cefoperazone with berberine pretreatment. This study represents a successful application of biliary microdialysis sampling technique, which is feasible for pharmacokinetic and biliary drug excretion studies.

Voltammetric studies on the antibiotic drug cefoperazone quantification and pharmacokinetic studies.

A fully validated simple, sensitive and selective square-wave stripping voltammetry procedure was described for the trace quantification of cefoperazone in bulk form, formulations and human serum/plasma. The procedure was based on reduction of the adsorbed drug onto a hanging mercury drop electrode. The procedural conditions were optimized as: frequency=60Hz, scan increment=8mV, pulse amplitude=25mV, preconcentration potential=-0.3V (versus Ag/Ag/KCl(s)), preconcentration duration=60-150s and an acetate buffer of pH 4.2 as a supporting electrolyte. A limit of detection of 4.5x10(-10)M and a limit of quantitation of 1.5x10(-9)M bulk cefoperazone were achieved following preconcentration of the drug onto the hanging mercury drop electrode for 150s. The proposed square-wave adsorptive cathodic stripping voltammetric procedure was successfully applied for trace quantification of cefoperazone in human serum and plasma. The achieved limits of detection and quantitation of the drug in human serum were 6x10(-10)M (0.375ngml(-1)) and 2x10(-9)M (1.250ngml(-1)), respectively. The pharmacokinetic parameters of cefoperazone in plasma of hospitalized volunteers were successfully estimated.

Pharmacodynamics and pharmacokinetics of cefoperazone and cefamandole in dogs following single dose intravenous and intramuscular administration.

The pharmacokinetics and intramuscular (i.m.) bioavailability of cefoperazone and cefamandole (20mg/kg) were investigated in dogs and the findings related to minimal inhibitory concentrations (MICs) for 90 bacterial strains isolated clinically from dogs. The MICs of cefamandole for Staphylococcus intermedius (MIC(90) 0.125 microg/mL) were lower than those of cefoperazone (MIC(90) 0.5 micro/mL) although the latter was more effective against Escherichia coli strains (MIC(90) 2.0 microg/mL vs. 4.0 microg/mL). The pharmacokinetics of the drugs after intravenous administrations were similar: a rapid distribution phase was followed by a slower elimination phase (t((1/2)lambda2) 84.0+/-21.3 min for cefoperazone and 81.4+/-9.7 min for cefamandole). The apparent volume of distribution and body clearance were 0.233 L/kg and 1.96 mL/kg/min for cefoperazone, 0.190 L/kg and 1.76 mL/kg/min for cefamandole. After i.m. administration the bioavailability and peak serum concentration of cefamandole (85.1+/-13.5% and 35.9+/-5.4 microg/mL) were significantly higher than cefoperazone (41.4+/-7.1% and 24.5+/-3.0 micog/mL), but not the serum half-lives (t(1/2el) 134.3+/-12.6 min for cefoperazone and 145.4+/-12.3 min for cefamandole). The time above MIC(90) indicated that cefamandole can be administered once daily to dogs for the treatment of staphylococcal infections (T>MIC for S. intermedius 23.8+/-0.3 and for Staphylococcus aureus 21.6+/-0.6h).

In vitro and in situ evidence for the contribution of Labrasol and Gelucire 44/14 on transport of cephalexin and cefoperazone by rat intestine.

In vitro and in situ intestinal transport of beta-lactam antibiotics in the presence of two novel pharmaceutical excipients, caprylocaproyl and lauroyl macrogolglycerides (Labrasol and Gelucire 44/14), is described. The objective was to compare the effects of both macrogolglycerides on the intestinal transport of cephalexin, a substrate of oligopeptide transporters, and cefoperazone, a non-substrate of them. The in vitro transport studies were performed using a sheet of rat jejunum mounted in Ussing-type diffusion chambers. The in situ studies used an isolated internal loop model in the rat. Labrasol and Gelucire 44/14 were used as the excipients at low concentrations (0.01-0.5%, w/v). The membrane permeability of both drugs was compared by apparent permeability coefficients (P(app)) determined from changes in the amount of permeation vs. time in in vitro studies and by apparent absorptive clearance (CL(app)) determined from changes in the steady state drug concentration of perfusate in in situ studies. The P(app) value of cephalexin increased with an increase in the concentration of Labrasol (0.05-0.5%) compared to the value without Labrasol. The enhancing effect of Labrasol on cephalexin transport was similarly observed in in situ studies, and when 0.5% Labrasol was used in the presence of glycyl-L-leucine or L-alanyl-L-alanine, 60 or 46% enhancement of the active transport of cephalexin by Labrasol was obtained. On the other hand, Gelucire 44/14 did not affect the P(app) and CL(app) of either drug. The different effects of the excipients on cephalexin transport were thought to be due to the influences of size parameters such as a polydispersity index and particle size, and the change in the short-circuit current of jejunum by the addition of the excipient.

Pharmacokinetics of cefoperazone and sulbactam in liver transplant patients.

The authors evaluated the pharmacokinetics of cefoperazone and sulbactam in 9 liver transplant patients. Cefoperazone and sulbactam were administered as an intravenous infusion over 30 minutes every 12 hours for six doses, and multiple blood samples were collected immediately after the first dose (administered during the surgery) and after the last dose. The concentrations of cefoperazone and sulbactam in serum and, when possible, in urine and bile collected over one dosing interval were measured by high-pressure liquid chromatography. The concentration of cefaperazone ranged from 436 to 4118 microg/ml, and sulbactam ranged from 3.3 to 8.7 microg/ml in the bile samples. The intraoperative clearance of cefoperazone (0.53+/-0.18 ml/min/kg) was significantly higher than the postoperative clearance (0.21+/-0.23 ml/min/kg). The half-life of cefaperazone, although not statistically significantly different, was prolonged in all patients during the postoperative period. The clearance of sulbactam (1.51+/-0.51 ml/min/kg) was lower than what is reported in patients with normal renal function but was comparable to what has been reported in patients with renal impairment and in critically ill patients. There were no significant differences in any of the pharmacokinetic parameters of sulbactam during and after surgery. The pharmacokinetic parameters of cefoperazone and sulbactam were significantly altered in liver transplant patients compared to what has been reported in normal subjects but were similar to what has been reported in patients with liver and renal impairment. There was a significant impairment in the biliary excretion of cefoperazone during the postoperative period in liver transplant patients. Although the percentage of the dose of cefoperazone excreted in the bile was drastically reduced, the biliary concentrations were generally high and above the MIC for most organisms. Given that both renal and hepatic elimination of cefoperazone is decreased, leading to a lower clearance and longer half-life in liver transplant patients, lower doses (1-2 g per day) of cefoperazone may be sufficient in liver transplant patients during the immediate postoperative period.

In vitro antibiotic release from poly(3-hydroxybutyrate-co-3-hydroxyvalerate) rods.

Provision and maintenance of adequate concentrations of antibiotics at infection sites is very important in treating highly resistant infections. For diseases like implant related osteomyelitis (IRO) it is best to provide this locally via implanted drug formulations, as systemic administration of the antibiotic may not be effective due to damaged vasculature. In this study, poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) rods containing 7, 14 and 22% (mol) 3-hydroxyvalerate were loaded with sulbactam:cefoperazone or gentamicin, and their antibiotic release behaviours were studied under in vitro conditions in physiological phosphate buffer at room temperature. The release patterns were representative of release from monolithic devices where a rapid early release phase is followed by a slower and prolonged release. With PHBV 22 rods, the latter phase continued for approximately 2 months. This duration is critical because a proper antibiotic therapy of IRO requires the minimal effective concentration for at least 6 weeks. After in vitro release, voids with sharp edges were detected on the rods, indicating that the drug crystals dissolved but the polymer did not undergo erosion within this test period. Changing the polymer:drug ratio from 2:1 to 20:1 substantially decreased the drug release rate. A change of polymer type, however, did not lead to any detectable changes in the release patterns. Gentamicin release also followed a similar pattern, except that the concentration of the drug in the release medium exhibited a decrease after long release periods, indicating degradation (or decomposition) of the antibiotic in the release medium.

The penetration of cefoperazone and sulbactam into the lumbar intervertebral discs.

Six patients received 1 g and six other patients received 2 g of cefoperazone and sulbactam 15 minutes before lumbar disc surgery. Liquid chromatographic analysis of disc tissue revealed that only patients receiving the 2-g dose had mean tissue levels above the minimum inhibitory concentration for Staphylococcus aureus and epidermidis.