Pharmacodynamic Evaluation of Ampicillin-sulbactam in Pediatric Patients Using Plasma and Urine Data.

BACKGROUND: We aimed to develop population pharmacokinetic (PK) models of ampicillin and sulbactam using pooled data analysis and to optimize dosing regimens of ampicillin-sulbactam (combination ratio of 2:1) in pediatric patients. METHODS: Population PK models of ampicillin and sulbactam were separately developed by simultaneously fitting plasma and urine data from pediatric patients in 14 published studies. Based on these models, we estimated the probability of attaining a pharmacodynamic (PD) target [50% of time that free drug concentrations above the minimum inhibitory concentration, 50% fT > minimum inhibitory concentration (MIC)] against MIC90 [MIC that blocked the growth of 90% of the strains] of common bacteria in community-acquired pneumonia. RESULTS: The analysis included 54 pediatric patients (0.083-16.42 years of age, 4.0-77.0 kg of body weight). A total of 284 plasma concentrations and 90 urinary excretions from 0 to 6 hours after administration were used for population PK modeling. The data were adequately described by 2-compartment models for ampicillin and sulbactam. Age was not a statistically significant covariate in the PK of either drug. The PK/PD breakpoint MICs for 45 mg/kg 3 times daily and 75 mg/kg 4 times daily (q.i.d.) were 0.25 and 1 µg/mL, respectively. For empiric therapy of community-acquired pneumonia, because MIC90 values for the main target pathogens is high (MIC90 = 2 µg/mL for Streptococcus pneumoniae and MIC90 = 4 µg/mL for Haemophilus influenzae), 75 mg/kg q.i.d. (Food and Drug Administration-approved maximum dosage in United States) might be better than 45 mg/kg 3 times daily (within approved dosage in Japan) to cover many pathogens. CONCLUSIONS: From the results of this PK/PD approach, 75 mg/kg q.i.d. (Food and Drug Administration-approved maximum dosage) should be recommended in the empiric therapy of community-acquired pneumonia.

Sex-specific and concentration-dependent influence of Cremophor RH 40 on ampicillin absorption via its effect on intestinal membrane transporters in rats.

Pharmaceutical excipients are the basic materials and important components of pharmaceutical preparations, and play an important role in improving the efficacy of drugs and reducing adverse reactions. Therefore, selecting suitable excipients for dosage form is an important step in formulation development. An increasing number of studies have revealed that the traditionally regarded "inert" excipients can, however, influence the bioavailability of drugs. Moreover, these effects on the bioavailability of drugs caused by pharmaceutical excipients may differ in between males and females. In this study, the in situ effect of the widely-used pharmaceutical excipient Cremophor RH 40 spanning from 0.001% to 0.1% on the intestinal absorption of ampicillin in male and female rats using closed-loop models was investigated. Cremophor RH 40 ranging from 0.03% to 0.07% increased the absorption of ampicillin in females, however, was decreased in male rats. The mechanism of such an effect on drug absorption is suggested to be due to the interaction between Cremophor RH 40 and two main membrane transporters P-gp and PepT1. Cremophor RH 40 altered the PepT1 protein content in a sex-dependent manner, showing an increase in female rats but a decrease in males. No modification on the PepT1 mRNA abundance was found with Cremophor RH 40, indicating that the excipient may regulate the protein recruitment of the plasma membrane from the preformed cytoplasm pool to alter the PepT1 function. This influence, however, may differ between males and females. As such, the study herein shows that supposedly inert excipient Cremophor RH 40 can influence membrane fluidity, uptake and efflux transporters in a sex- and concentration-dependent manner. These findings, therefore, highlight the need for sex-specific studies in the application of solubilizing excipients in drug formulation development.

Dosing Optimization of Ampicillin-Sulbactam Based on Cystatin C in Elderly Patients with Pneumonia.

Ampicillin-sulbactam is a first-line therapy for pneumonia and is mainly excreted by the kidney. It is important to optimize the dose and dosing interval of ampicillin-sulbactam because in patients with decreased renal function and low skeletal muscle mass, such as the elderly, excess drug may burden renal function. In this study, we evaluated indices of renal function and optimized the dose and dosing interval of ampicillin-sulbactam based on pharmacokinetics (PK) and pharmacodynamics theory in elderly patients. The serum concentrations of ampicillin and sulbactam were measured by HPLC, and PK parameters were calculated. Correlations between the clearance of ampicillin or sulbactam and renal function were evaluated, and dosing optimization was calculated based on PK parameters. The PK parameters of ampicillin were CL = 6.5 ± 4.0 L/h, Vd = 19.3 ± 0.2 L, Ke = 0.4 ± 0.2, and t1/2 = 2.7 ± 1.6 h. The most correlated renal function index was estimated glomerular filtration rate (eGFRcys-c) calculated by serum cystatin-c (r = 0.7374, correlation formula; CL of ampicillin = 0.1937 × eGFRcys-c-0.6726). Based on this formula, we calculated the clearance of ampicillin and developed dosing regimens for the elderly. Serum cystatin-c concentration is an ideal index to optimize ampicillin-sulbactam antimicrobial therapy in elderly patients with pneumonia.

Effects of dosing frequency on the clinical efficacy of ampicillin/sulbactam in Japanese elderly patients with pneumonia: A single-center retrospective observational study.

This study sought to investigate whether dosing frequency (the number of doses per day) affects the antimicrobial efficacy and safety of ampicillin/sulbactam (ABPC/SBT) in Japanese elderly pneumonia patients treated with ABPC/SBT at 6 g/day. This was a retrospective observational study that included hospitalized elderly patients (aged ≥75 years, 10 ml/min ≤CLcr <50 ml/min) who received 3 g every 12 h (BID; n = 61) or 1.5 g every 6 h (QID; n = 45) for the treatment of pneumonia. The primary endpoint was clinical response, assessed by measuring body temperature, white blood cell count, and C-reactive protein levels. Pharmacokinetic and pharmacodynamic simulations were conducted in silico to rationalize the clinical findings. The clinical response rates (extremely effective and effective) in the BID and QID groups were 36.1% and 55.6%, respectively (p = .0459). QID tended to be more effective in patients with gram-negative rods detected (p = .0563). According to the simulated minimum plasma ABPC concentrations at steady state for BID and QID were 2.5 and 7.3 µg/ml, respectively (p < .0001). Based on the simulated time above minimum inhibitory concentration (MIC), pharmacological (not clinical) efficacy was predicted to be higher with QID. Both groups had similar safety profiles. The main adverse event in both groups was liver damage. The present retrospective survey demonstrated that ABPC/SBT treatment for elderly patients with pneumonia and renal dysfunction was more effective with QID than with BID. Therefore, the QID regimen is worthy of consideration to improve the clinical outcomes of ABPC/SBT therapy in the present patient population.

Ampicillin Pharmacokinetics During First Week of Life in Preterm and Term Neonates.

BACKGROUND AND AIMS: Ampicillin is 1 of the most commonly used antibiotics for treatment of early onset sepsis, but its pharmacokinetics (PK) is poorly characterized. We aimed to define the dose of ampicillin for late preterm and term neonates by evaluating its PK in serum, cerebrospinal (CSF), and epithelial lining fluid. METHODS: A prospective study included neonates receiving ampicillin for suspected or proven early onset sepsis and pneumonia. PK samples were collected at steady state, at predose and 5 minutes, 1 hour, 3 hours, 8 hours, and 12 hours after ampicillin 3-minute infusion. Ampicillin concentrations were measured by ultra-high-performance liquid chromatography. Noncompartmental anaysis (NCA) and population pharmacokinetic (pop-PK) modeling were performed and probability of therapeutic target attainment was simulated. RESULTS: In 14 neonates (GA of 32-42 wks; mean BW 2873 g), PK parameters (mean ± SD) in NCA were the following: half-life 7.21 ± 7.97 hours; volume of distribution (Vd) 1.07 ± 0.51 L; clearance (CL) 0.20 ± 0.13 L/h; 24-hour area under the concentration-time curve 348.92 ± 114.86 mg*h/L. In pop-PK analysis, a 2-compartmental model described the data most adequately with the final parameter estimates of CL 15.15 (CV 40.47%) L/h/70kg; central Vd 24.87 (CV 37.91%) L/70kg; intercompartmental CL 0.39 (CV 868.56) L/h and peripheral Vd 1.039 (CV 69.32%) L. Peutic target attainment simulations demonstrated that a dosage of 50 mg/kg q 12 hours attained 100% fT > MIC 0.25 mg/L, group B streptococcal breakpoint. CONCLUSIONS: We recommend ampicillin dosage 50 mg/kg q 12 hours for neonates with gestational age ≥32 weeks during the first week of life.

Evaluation of hyaluronic acid nanoparticle embedded chitosan-gelatin hydrogels for antibiotic release.

The development of chitosan-gelatin (CS-G) hydrogels embedded with ampicillin-loaded hyaluronic acid nanoparticles (HA-NPs) for wound dressing is proposed. It was aimed to provide controlled ampicillin delivery by incorporation of HA-NPs into biocompatible CS-G hydrogel structure. According to in vitro ampicillin release studies, 55% of ampicillin was released from CS-G/HA-NPs hydrogels after 5 days. Antibacterial performance of CS-G/HA-NPs hydrogels was proven with agar disc diffusion test. For cytotoxicity assay, fibroblast cell viability increased in CS-G/HA-NPs hydrogels compared with CS-G group after 24 hr incubation. Consequently, the potential ability of CS-G/HA-NPs hydrogels as a controlled drug delivery system has been verified.

Prostatic Pharmacokinetic/Pharmacodynamic Evaluation of Ampicillin-Sulbactam for Bacterial Prostatitis and Preoperative Prophylaxis.

This study aims to define the penetration of ampicillin and sulbactam into prostate tissue, develop a prostatic pharmacokinetic model of each drug, and assess the appropriateness of ampicillin-sulbactam regimens for the treatment of prostatitis and the prophylaxis of postoperative infection, based on a pharmacokinetic and pharmacodynamic simulation. Subjects were prostatic hyperplasia patients prophylactically receiving a 0.5-hour infusion of 1.5 g (1:0.5 g) or 3 g (2:1 g) ampicillin-sulbactam before transurethral resection of the prostate. Ampicillin and sulbactam concentrations in plasma and prostate tissue were measured. The prostate tissue/plasma ratios of both ampicillin and sulbactam were approximately 0.37 (area under the drug concentration-time curve), and penetration was similar. The prostatic population pharmacokinetic model, which included a covariate analysis, adequately predicted prostate tissue concentrations in our patient population. For therapeutic use, aiming for a bactericidal target of 50% of time above minimum inhibitory concentration (T > MIC) in prostate tissue, 3 g ampicillin-sulbactam 4 times daily achieved ≥90% expected probability against only Enterococcus faecalis in typical patients with a creatinine clearance (CLcr ) of 30 mL/min. For prophylactic use, aiming for a bacteriostatic target of 30% T > MIC, 3 g ampicillin-sulbactam 4 times daily achieved ≥90% expected probability of attaining the bacteriostatic target against E. faecalis and Proteus species when CLcr was 30 mL/min. Based on prostatic simulations, the present study provides helpful recommendations for the treatment of bacterial prostatitis and preoperative prophylaxis in prostatectomy.

A new pharmacodynamic approach to study antibiotic combinations against enterococci in vivo: Application to ampicillin plus ceftriaxone.

The combination of ampicillin (AMP) and ceftriaxone (CRO) is considered synergistic against Enterococcus faecalis based on in vitro tests and the rabbit endocarditis model, however, in vitro assays are limited by the use of fixed antibiotic concentrations and the rabbit model by poor bacterial growth, high variability, and the use of point dose-effect estimations, that may lead to inaccurate assessment of antibiotic combinations and hinder optimal translation. Here, we tested AMP+CRO against two strains of E. faecalis and one of E. faecium in an optimized mouse thigh infection model that yields high bacterial growth and allows to define the complete dose-response relationship. By fitting Hill's sigmoid model and estimating the parameters maximal effect (Emax) and effective dose 50 (ED50), the following interactions were defined: synergism (Emax increase ≥2 log10 CFU/g), antagonism (Emax reduction ≥1 log10 CFU/g) and potentiation (ED50 reduction ≥50% without changes in Emax). AMP monotherapy was effective against the three strains, yielding valid dose-response curves in terms of dose and the index fT>MIC. CRO monotherapy showed no effect. The combination AMP+CRO against E. faecalis led to potentiation (59-81% ED50 reduction) and not synergism (no changes in Emax). Against E. faecium, the combination was indifferent. The optimized mouse infection model allowed to obtain the complete dose-response curve of AMP+CRO and to define its interaction based on pharmacodynamic parameter changes. Integrating these results with the pharmacokinetics will allow to derive the PK/PD index bound to the activity of the combination, essential for proper translation to the clinic.

Paradoxical Antibiotic Effect of Ampicillin: Use of a Population Pharmacokinetic Model to Evaluate a Clinical Correlate of the Eagle Effect in Infants With Bacteremia.

BACKGROUND: High doses of ampicillin are often used to achieve therapeutic drug concentrations in infants. A paradoxical antibiotic effect, often called the Eagle effect, occurs when increasing concentrations of antibiotic above a threshold results in decreased efficacy. It is unknown if infants treated with ampicillin are at risk for this paradoxical effect. METHODS: We identified infants <28 days of age with Escherichia coli, Enterococcus or Streptococcus agalactiae (group B streptococcus) bloodstream infections from 1997 to 2012 and previously included in an ampicillin pharmacokinetic (PK) modeling study. We compared the odds of death for ampicillin dose, estimated time above the minimum inhibitory concentration (T > MIC) and PK parameters using separate logistic regression models. Adjusted logistic regression and Poisson models were used to calculate the odds of prolonged bacteremia ≥3 days and the duration of bacteremia, respectively, for dose, T > MIC and multiple PK parameters. RESULTS: Among 1272 infants meeting inclusion criteria, odds of death 7 or 30 days after the positive blood culture were not consistent with a paradoxical effect across any of the dosing regimens or PK parameters evaluated. The odds of prolonged bacteremia was lowest at the lowest dose category and the lowest daily dose category but not associated with the area-under-the-concentration time curve from 0 to 24 hours, or the maximum or minimum concentrations at steady state. T > MIC of ≥50% of the dosing interval was associated with decreased duration of bacteremia and odds of prolonged bacteremia. CONCLUSIONS: It is unlikely that a paradoxical antibiotic effect will have a clinical correlate when ampicillin is used for neonatal bacteremia. A T > MIC ≥50% decreased both duration of bacteremia and odds of prolonged bacteremia.

Effect of drug combinations on the kinetics of antibiotic resistance emergence in Escherichia coli CFT073 using an in vitro hollow-fibre infection model.

Antibiotic resistance is one of the major threats to public health today. To address this problem requires an urgent comprehensive approach. Strategic and multitargeted combination therapy has been increasingly used clinically to treat bacterial infections. The hollow-fibre infection model (HFIM) is a well-controlled in vitro bioreactor system that is increasingly being used in the assessment of resistance emergence with monotherapies and combination antibiotic therapies. In this study, the HFIM was evaluated as a reliable in vitro method to quantitatively and reproducibly analyse the emergence of antibiotic resistance using ampicillin, fosfomycin and ciprofloxacin and their simultaneous combinations against Escherichia coli CFT073, a clinical uropathogenic strain. Bacteria were exposed to clinically relevant pharmacokinetic (PK) concentrations of the drugs for 10 days. Drug and bacterial samples were collected at different time points for PK analysis and to enumerate total and resistant bacterial populations, respectively. The results demonstrated that double or triple combinations significantly delayed the emergence of resistant E. coli CFT073 subpopulations. These findings suggest that strategic combinations of antimicrobials may play a role in controlling the emergence of resistance during treatment. Further animal and human trials will be needed to confirm this and to ensure that there is no adverse impact on the host microbiome or unexpected toxicity. The HFIM system could potentially be used to identify clinically relevant combination dosing regimens for use in a clinical trial evaluating the appearance of resistance to antibacterial drugs.

Tuning the mechanical and physicochemical properties of cross-linked protein films.

Films derived from natural sources such as proteins provide an advantage over synthetic films due to their noncytotoxicity, biodegradability, and vast functionality. A new protein source gained from the cataractous eye protein isolate (CEPI) obtained after surgery has been investigated for this purpose. Glycerol has been employed as the plasticizer and glutaraldehyde (GD) as a cross-linker. Fourier transform infrared spectroscopy was employed to characterize the films. Nanoindentation and thermogravimetric analyses reveal improved mechanical and thermal properties of the cross-linked films. The films with 20% (w/w) GD exhibited properties such as the highest modulus and low water solubility. It is possible to tune the properties based on the extent of cross-linking. All the films were completely degraded by the enzyme trypsin. The similarity of these films was checked by using the prepared films as a delivery vehicle for a model compound, ampicillin sodium. The encapsulation efficiency was found to be 74%, and in vitro release studies showed significant amounts of drug release at physiological pH. This study will help us understand how the properties of protein films can be tuned to obtain the desired physicochemical properties. These biodegradable protein films could find use in pharmaceutical industries as delivery carriers.

High-resolution experimental and computational electrophysiology reveals weak ß-lactam binding events in the porin PorB.

The permeation of most antibiotics through the outer membrane of Gram-negative bacteria occurs through porin channels. To design drugs with increased activity against Gram-negative bacteria in the face of the antibiotic resistance crisis, the strict constraints on the physicochemical properties of the permeants imposed by these channels must be better understood. Here we show that a combination of high-resolution electrophysiology, new noise-filtering analysis protocols and atomistic biomolecular simulations reveals weak binding events between the ß-lactam antibiotic ampicillin and the porin PorB from the pathogenic bacterium Neisseria meningitidis. In particular, an asymmetry often seen in the electrophysiological characteristics of ligand-bound channels is utilised to characterise the binding site and molecular interactions in detail, based on the principles of electro-osmotic flow through the channel. Our results provide a rationale for the determinants that govern the binding and permeation of zwitterionic antibiotics in porin channels.

The kinetics of TEM1 antibiotic degrading enzymes that are displayed on Ure2 protein nanofibrils in a flow reactor.

Enzymatic functionalization of cross-ß structured protein nanofibrils has hitherto resulted in a severe reduction of the catalytic efficiency of high turnover biocatalysts. It has been speculated that steric restrictions and mass transport pose limits on the attached enzymes, but detailed kinetics analyzing this have not yet been reported. For a more comprehensive understanding, we studied protein nanofibrils endowed with TEM1, a ß-lactamase from Escherichia coli. The packing density of TEM1 along the fibrils was controlled by co-fibrillation; in other words, the N-terminal ureidosuccinate transporter Ure2(1-80) from Saccharomyces cerevisiae was simultaneously aggregated with the chimeric proteins TEM1-Ure2(1-80). The mature fibrils were trapped in a column, and the rate of ampicillin hydrolysis was recorded using a continuous substrate flow. The turnover rate was plotted as a function of substrate molecules available per enzyme per second, which demonstrated that an elevated substrate availability counteracts mass transport limitations. To analyze this data set, we derived a kinetic model, which makes it possible to easily characterize and compare enzymes packed in columns. The functional TEM1 nanofibrils possess 80% of the catalytic turnover rate compared to free TEM1 in solution. Altogether, we have created protein nanofibrils that can effectively hydrolyze ß-lactam antibiotic contaminations and provided a groundwork strategy for other highly functional enzymatic nanofibrils.

A comparative study of single-needle and coaxial electrospun amyloid-like protein nanofibers to investigate hydrophilic drug release behavior.

In this study, nanofibers containing an amyloid-like bovine serum albumin (AL-BSA) carrier and a model drug (ampicillin) were produced by electrospinning. The release behavior of ampicillin was compared from electrospun nanofibers prepared as either coaxial or single-needle types. SEM images showed that the membranes had a uniform and smooth structure and the core/shell fibers were found to be thicker than the core fibers. Core/shell production was proved by transmission electron microscopy images. Fourier transform infrared spectroscopy indicated the existence of compatibility between ampicillin and the AL-BSA matrix. The in vitro antimicrobial properties of ampicillin were studied through the comparison of bacterial inhibition zones and ampicillin was found to be more effective against Gram-positive Staphylococcus aureus than Gram-negative Escherichia coli. Moreover, in vitro drug release tests were conducted to explore the relationship between the shell thickness and the drug release rate. A burst release was observed for all membranes owing to the small fiber diameters and thus short diffusion lengths. For core membranes, the drug release mechanism followed Fickian transport, which was close to zero-order kinetic. A typical biphasic release mechanism was observed for the core/shell nanofibers. Overall, we present the first evidence of AL-BSA as a potential core/shell drug mediator.

Novel pH sensitive dual drug loaded-gelatin methacrylate/methacrylic acid hydrogel for the controlled release of antibiotics.

The aim of the present study was to develop a novel pH sensitive gelatin methacrylate hydrogel for the controlled delivery of Gentamicin (GS) and Ampicillin (Amp). GS and Amp having synergistic activity is effective in killing multi drug resistant bacteria. The hydrogel was well characterized using FTIR, XRD and SEM techniques. The drug loading and encapsulation efficiency were found to be 85.0 and 77.0% for GS, 79.0 and 88.0% for Amp, respectively. The in vitro swelling, degradation and release profiles suggest the pH dependent behaviour of hydrogel. DPPH Assay confirmed the role of 2-amino guanidine in nullifying the side effect of GS and inhibition percentage of DDLHG is found to be 85.0%. Antimicrobial studies revealed the increased efficiency of the drug combination in killing bacteria.

Comparative Analysis of Ampicillin Plasma and Dried Blood Spot Pharmacokinetics in Neonates.

BACKGROUND: Dried blood spot (DBS) is a practical sampling strategy for pharmacokinetic studies in neonates. The utility of DBS to determine the population pharmacokinetics (pop-PK) of ampicillin, as well as accuracy versus plasma samples, was evaluated. METHODS: An open-label, multicenter, opportunistic, prospective study was conducted in neonates. Ampicillin concentrations from plasma and DBS (CONCPlasma and CONCDBS) were measured by liquid chromatographic tandem mass spectrometry and analyzed using pop-PK and statistical (including transformation) approaches. RESULTS: A total of 29 paired plasma and DBS samples from 18 neonates were analyzed. The median (range) gestational age and postnatal age were 37 (27-41) weeks and 8 (1-26) days, respectively. The geometric mean of CONCDBS to CONCPlasma ratio was 0.56. Correlation analysis demonstrated strong association between CONCPlasma and CONCDBS (r = 0.902, analysis of variance P < 0.001). Using linear regression transformation, the estimated CONCPlasma (eCONCPlasma) was derived using (CONCDBS - 3.223)/0.51. The median bias and geometric mean ratio improved to -11% and 0.88 (Wilcoxon signed-rank test, P < 0.001), respectively, when comparing eCONCPlasma to CONCPlasma. Furthermore, using pop-PK modeling, the median bias (interquartile range) for clearance and individual predicted concentrations improved to 8% (-11 to 50) and -8% (-34 to 11), respectively, when eCONCPlasma was used. CONCLUSIONS: After transformation, DBS sampling accurately predicted ampicillin exposure in neonates.

Are postnatal ampicillin levels actually related to the duration of intrapartum antibiotic prophylaxis prior to delivery? A pharmacokinetic study in 120 neonates.

OBJECTIVE: To assess ampicillin levels according to the duration of intrapartum antibiotic prophylaxis (IAP). DESIGN: Prospective cohort single-centre study. SETTING: Tertiary care centre (Modena, Italy). PATIENTS: 120 neonates≥35 weeks' gestation exposed to IAP. INTERVENTIONS: Neonates were divided into four groups, according to the duration of IAP prior to delivery: group 1 (n=30; <1 hour), group 2 (n=30; ≥1 and <2 hours), group 3 (n=30; ≥2 and <4 hours) and group 4 (n=30; ≥2 doses, ≥4 hours). MAIN OUTCOME MEASURES: Blood samples were collected at delivery (from the umbilical cord) and at age 4 hours (from a peripheral vessel). RESULTS: Median duration of IAP was 121 min (range 7-2045 min). Median ampicillin levels in umbilical cord blood were 10.4 µg/mL (IQR 6.4-14.9) and in peripheral blood were 4.7 µg/mL (IQR 2.8-6.4µg/mL). Umbilical cord blood levels reached a peak approximately 30 min after IAP and then declined significantly (p<0.001). Peripheral blood levels did not differ among study groups. Neonates exposed to a full loading dose (n=115) had peripheral blood levels 2.5-70 times higher than the minimal inhibitory concentration for group B streptococcus. There was no relationship between neonatal ampicillin concentrations and the duration of IAP prior to delivery (ß=-0.0003, 95% CI -0.02 to 0.001, p=0.680). CONCLUSIONS: Ampicillin levels reach a peak in the umbilical cord blood within 30 min of intrapartum administration. After a full loading dose, bactericidal levels persist for at least 4 hours after birth and seem independent of the duration of IAP prior to delivery.

Pharmacokinetics of ampicillin-sulbactam in serum and synovial fluid samples following regional intravenous perfusion in the distal portion of a hind limb of adult cattle.

OBJECTIVE To describe concentration-over-time data for ampicillin and sulbactam in the digital and systemic circulations and synovial fluid (SYN) of cattle following a single injection of ampicillin-sulbactam as a regional IV perfusion (RIVP). ANIMALS 6 healthy adult nonlactating Jersey-crossbred cows. PROCEDURES The right hind limb of each cow was aseptically prepared. A tourniquet was applied around the midmetatarsal region, and 1.0 g of ampicillin with 0.5 g of sulbactam in a combined formulation was administered as an RIVP into the dorsal common digital vein (DCDV). Blood samples from the DCDV and jugular vein and SYN samples from the metatarsophalangeal joint of the prepared limb were collected immediately before and at predetermined times for 24 hours after RIVP. One blood sample was obtained from the abaxial proper plantar vein of the lateral digit of the prepared limb 0.25 hours after RIVP. Serum and SYN ampicillin and sulbactam concentrations were determined by high-performance liquid chromatography. RESULTS Mean ± SD maximum concentration of ampicillin in SYN and serum obtained from the abaxial proper plantar and jugular veins was 1,995 ± 1,011 µg/mL, 5,422 ± 1,953 µg/mL, and 2.5 ± 1.6 µg/mL, respectively. Corresponding serum and SYN concentrations of sulbactam were lower but followed the same pattern over time as those for ampicillin. Synovial fluid ampicillin concentration remained above 8 µg/mL for a mean time of 18.9 hours. CONCLUSIONS AND CLINICAL RELEVANCE Potentially therapeutic concentrations of ampicillin were achieved in regional serum and SYN samples; SYN concentrations remained at potentially therapeutic values for > 12 hours following RIVP of 1.5 g of ampicillin-sulbactam in the hind limb of healthy cows.

Excipient-mediated alteration in drug bioavailability in the rat depends on the sex of the animal.

The pharmaceutical excipient, polyethylene glycol 400 (PEG 400), unexpectedly alters the bioavailability of the BCS class III drug ranitidine in a sex-dependent manner. As ranitidine is a substrate for the efflux transporter P-glycoprotein (P-gp), we hypothesized that the sex-related influence could be due to interactions between PEG 400 and P-gp. In this study, we tested this hypothesis by: i) measuring the influence of PEG 400 on the oral bioavailability of another P-gp substrate (ampicillin) and of a non-P-gp substrate (metformin); and ii) measuring the effect of PEG 400 on drug bioavailability in the presence of a P-gp inhibitor (cyclosporine A) in male and female rats. We found that PEG 400 significantly increased (p<0.05) the bioavailability of ampicillin (the P-gp substrate) in male rats, but not in female ones. In contrast, PEG 400 had no influence on the bioavailability of the non-P-gp substrate, metformin in male or female rats. Inhibition of P-gp by oral pre-treatment with cyclosporine A increased the bioavailability of the P-gp substrates (ampicillin and ranitidine) in males and females (p<0.05), and to a greater extent in males, but had no influence on the bioavailability of metformin in either male or female rats. These results prove the hypothesis that the sex-specific effect of PEG 400 on the bioavailability of certain drugs is due to the interaction of PEG 400 with the efflux transporter P-gp.