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.

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.

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.

LC-MS/MS measurement of ampicillin residue in chicken tissues at 2 days after in-feed administration.

We assessed ampicillin (ABPC) concentrations of liver, kidney and skin at a 2-day withdrawal period in ten male and ten female White Leghorn chickens fed the diet containing ABPC (ABPC medicated feed 40 mg/kg body weight/day) for a week. The ABPC residues were measured with liquid chromatography-tandem mass spectrometry and the mean recoveries and quantitation limits ranged from 93.0% to 102.7% and from 0.1 to 1.4 ng/g, respectively. The residual ABPC concentrations were ≤7.82 ng/g for the skin and ≤0.64 ng/g for the kidney, suggesting below the Japanese provisional maximum residue limits. These results revealed that the analytical method is developed for residue ABPC and that the withdrawal period is appropriate.

Modeling the growth dynamics of multiple Escherichia coli strains in the pig intestine following intramuscular ampicillin treatment.

BACKGROUND: This study evaluated how dosing regimen for intramuscularly-administered ampicillin, composition of Escherichia coli strains with regard to ampicillin susceptibility, and excretion of bacteria from the intestine affected the level of resistance among Escherichia coli strains in the intestine of nursery pigs. It also examined the dynamics of the composition of bacterial strains during and after the treatment. The growth responses of strains to ampicillin concentrations were determined using in vitro growth curves. Using these results as input data, growth predictions were generated using a mathematical model to simulate the competitive growth of E. coli strains in a pig intestine under specified plasma concentration profiles of ampicillin. RESULTS: In vitro growth results demonstrated that the resistant strains did not carry a fitness cost for their resistance, and that the most susceptible strains were more affected by increasing concentrations of antibiotics that the rest of the strains. The modeling revealed that short treatment duration resulted in lower levels of resistance and that dosing frequency did not substantially influence the growth of resistant strains. Resistance levels were found to be sensitive to the number of competing strains, and this effect was enhanced by longer duration of treatment. High excretion of bacteria from the intestine favored resistant strains over sensitive strains, but at the same time it resulted in a faster return to pre-treatment levels after the treatment ended. When the duration of high excretion was set to be limited to the treatment time (i.e. the treatment was assumed to result in a cure of diarrhea) resistant strains required longer time to reach the previous level. CONCLUSION: No fitness cost was found to be associated with ampicillin resistance in E. coli. Besides dosing factors, epidemiological factors (such as number of competing strains and bacterial excretion) influenced resistance development and need to be considered further in relation to optimal treatment strategies. The modeling approach used in the study is generic, and could be used for prediction of the effect of treatment with other drugs and other administration routes for effect on resistance development in the intestine of pigs.

Multistrain models predict sequential multidrug treatment strategies to result in less antimicrobial resistance than combination treatment.

BACKGROUND: Combination treatment is increasingly used to fight infections caused by bacteria resistant to two or more antimicrobials. While multiple studies have evaluated treatment strategies to minimize the emergence of resistant strains for single antimicrobial treatment, fewer studies have considered combination treatments. The current study modeled bacterial growth in the intestine of pigs after intramuscular combination treatment (i.e. using two antibiotics simultaneously) and sequential treatments (i.e. alternating between two antibiotics) in order to identify the factors that favor the sensitive fraction of the commensal flora. Growth parameters for competing bacterial strains were estimated from the combined in vitro pharmacodynamic effect of two antimicrobials using the relationship between concentration and net bacterial growth rate. Predictions of in vivo bacterial growth were generated by a mathematical model of the competitive growth of multiple strains of Escherichia coli. RESULTS: Simulation studies showed that sequential use of tetracycline and ampicillin reduced the level of double resistance, when compared to the combination treatment. The effect of the cycling frequency (how frequently antibiotics are alternated in a sequential treatment) of the two drugs was dependent upon the order in which the two drugs were used. CONCLUSION: Sequential treatment was more effective in preventing the growth of resistant strains when compared to the combination treatment. The cycling frequency did not play a role in suppressing the growth of resistant strains, but the specific order of the two antimicrobials did. Predictions made from the study could be used to redesign multidrug treatment strategies not only for intramuscular treatment in pigs, but also for other dosing routes.

Enterococcal endocarditis complicated with ruptured infected-intracranial aneurysm: with pharmacokinetic-pharmacodynamic documentation in proof of the successful antimicrobial treatment.

A 74-year-old man presented with sudden onset of aphasia and apraxia. Magnetic resonance image (MRI) of the brain disclosed a left frontal hemorrhage. The concomitant low grade fever suggestive of infection was unresponsive to cefazolin 1 g q12h, and refractory to piperacillin (PIPC) 2 g q8h. Blood culture grew enterococci, establishing together with echocardiography the diagnosis of infective endocarditis. The angiography revealed cerebral hemorrhage to have resulted from the rupture of the infected intracranial aneurysm. The antimicrobial therapy was switched to ampicillin (ABPC) 2 g q4h plus gentamicin (GM) 60 mg q8h. The positive blood culture was subsequently identified Enterococcus faecium to which the minimum inhibitory concentration (MIC) of PIPC, and ABPC was 16 mcg/mL, and 4 mcg/mL, respectively. The peak concentration of serum ABPC was 83.1, median 50.8, and trough 25.8 mcg/mL. Thus, the percent time > MIC for ABPC was 100%, and the time > minimum bactericidal concentration (MBC) as well. On the other hand, time > MIC for PIPC, was found nearly 30% in retrospective analysis using population pharmacokinetics. The neurological deficit of the patient was completely restored to the normal status after 4-weeks' antimicrobial therapy with ABPC plus GM, then he underwent cardiac surgery for valvular replacement, where microbiological culture of the resected valve was negative. The constellation of the clinical, pharmacological and microbiological outcome in our case provides scientific evidence that the antibiotic therapy given to our case is the best available strategy as an antimicrobial treatment of severe enterococcal endocarditis complicated by disseminated lesion as infected intracranial aneurysm.

Evaluation of solubility and partition properties of ampicillin-based ionic liquids.

In order to overcome the problems associated with low water solubility, and consequently low bioavailability of active pharmaceutical ingredients (APIs), herein we explore a modular ionic liquid synthetic strategy for improved APIs. Ionic liquids containing L-ampicillin as active pharmaceutical ingredient anion were prepared using the methodology developed in our previous work, using organic cations selected from substituted ammonium, phosphonium, pyridinium and methylimidazolium salts, with the intent of enhancing the solubility and bioavailability of L-ampicillin forms. In order to evaluate important properties of the synthesized API-ILs, the water solubility at 25 °C and 37 °C (body temperature) as well as octanol-water partition coefficients (Kow's) and HDPC micelles partition at 25 °C were measured. Critical micelle concentrations (CMC's) in water at 25 °C and 37 °C of the pharmaceutical ionic liquids bearing cations with surfactant properties were also determined from ionic conductivity measurements.

Microfluidic-assisted synthesis of hemispherical and discoidal chitosan microparticles at an oil/water interface.

This study reports a facile method for the synthesis of hemispherical and discoidal chitosan microparticles by a combination of microfluidic technology and gelation strategy at an oil/water interface. Utilizing microfluidic emulsification in a cross-junction channel, the formation of regular droplets was achieved. Following the ionic gelation procedure at the liquid-liquid interface of the gelling solution and oil solution in the reservoir pool, either hemispherical or discoidal chitosan microparticles were obtained. Special emphasis was put on the interface reaction of emulsion gelation parameters such as ionic crosslinkers, density modifiers, and surfactants, to tailor the morphologies of chitosan particles ranging from 160 to 750 µm. In addition, the proposed microfluidic device is capable of generating relatively uniform microparticles with a well-controllable shape and size. Being a simple, low-cost and high-throughput process is an added advantage. The synthesized hemispherical and discoidal chitosan microparticles can be applied to many applications in the pharmaceutical and biomedical arena.

Formulation development and in vitro and in vivo evaluation of membrane-moderated transdermal systems of ampicillin sodium in ethanol: pH 4.7 buffer solvent system.

The objective of the present study was to develop membrane-moderated transdermal systems of ampicillin sodium and to evaluate them with respect to various in vitro and in vivo parameters. The membrane-type transdermal systems were prepared using a drug with various antinucleant polymers-hydroxypropyl methylcellulose (HPMC), methylcellulose (MC), cellulose acetate phthalate, chitosan, sodium alginate (SA), and sodium carboxymethylcellulose-in an ethanol: pH 4.7 buffer volatile system by the solvent evaporation technique with HPMC as the rate-controlling membrane for all the systems. The swelling properties of the polymers were studied, and drug-polymer interaction studies were performed. The patches were subjected to various physicochemical studies, in vitro release studies, permeation studies, and skin irritation studies. The best patch among the formulations was selected for further in vivo studies. Compared to the other patches, SA exhibited the highest moisture content at 16%; a 21% moisture uptake was found with MC. The release and permeation of the drug from the SA patch was found to be the maximum. The in vivo study of the SA patch exhibited a peak plasma concentration C(max) of 126 microg/mL at T(max) 4 hours. Hence, it can be concluded that hydrophilic ampicillin sodium can be developed as a transdermal delivery system with SA that is an alternative to intravenous administration and has minimal adverse effects.

Efficacy of ampicillin combined with ceftriaxone and gentamicin in the treatment of experimental endocarditis due to Enterococcus faecalis with no high-level resistance to aminoglycosides.

OBJECTIVE: This study tests the usefulness of ceftriaxone combined with ampicillin as an alternative to ampicillin plus gentamicin for the treatment of experimental endocarditis due to Enterococcus faecalis without high-level resistance to aminoglycosides. It also determines whether adding ceftriaxone to ampicillin and gentamicin increases the effectiveness against experimental enterococcal endocarditis resulting from E. faecalis. METHODS: Animals with catheter-induced endocarditis were infected intravenously with 108 cfu of the EF91 strain of E. faecalis and were treated for 3 days with ampicillin 2 g every 4 h administered as 'human-like' (H-L) pharmacokinetics, plus gentamicin 1 mg/kg every 8 h H-L, or ceftriaxone 2 g every 12 h H-L alone or combined with gentamicin 6 mg/kg every 24 h administered subcutaneously. RESULTS: The results of therapy for experimental endocarditis resulting from EF91 showed that the combination of ampicillin plus ceftriaxone was as effective as ampicillin plus gentamicin. The triple combination did not improve on the overall efficacies of the two-drug combinations. CONCLUSIONS: Because of its lower nephrotoxicity, ampicillin plus ceftriaxone may be a useful alternative therapy for E. faecalis endocarditis in selected patients.

Effects of oils and pharmaceutical excipients on the bioavailability of ampicillin orally administered, different oily and aqueous suspensions in rabbit.

The in vivo bioavailability and in vitro drug-release studies of ampicillin trihydrate in different oily and aqueous suspensions have been investigated. In addition, partition, solubility, and rheological measurements have also been carried out. The in vivo experimental design was based on a 6 x 6 latin square using the rabbit as the test animal. The bioavailability of ampicillin was determined using the plasma levels, which were measured microbiologically. Results of the study showed that oily and sucrose-containing aqueous formulations enhanced the extent of ampicillin absorption, although not statistically significantly, but was close to the borderline of significance. Ampicillin appears to be absorbed at essentially the same rate from both aqueous and oily formulations. The latter showed plasma-level time curves with biphasic absorption and are likely to produce prolonged plasma concentrations of ampicillin because of the effects of enterohepatic recycling. Viscosity appears to play an insignificant role in the results obtained since the bioavailability parameters correlate poorly with the viscosity except Cmax. It is suggested that enhancement in the bioavailability of ampicillin is due to the decrease in the gut transit rate brought about by the oil which predominates and masks the other effects of viscosity and osmotic effects of sucrose. The existence of a correlation between the in vitro drug-release rate (t50%) and viscosity and the lack of a correlation between in vivo and in vitro parameters support the above suggestion and indicate that traditional dissolution rate tests, such as flask-stirrer method, are unsatisfactory as bioavailability indicators when applied to dosage forms that caused marked changes in physiological factors like GER and biliary excretion.

Pharmacokinetics of antibiotic prophylaxis in major orthopedic surgery and blood-saving techniques.

The pharmacokinetics of cefuroxime, cefotiam, cefamandole, and ampicillin/sulbactam were randomly measured in 40 patients undergoing major orthopedic surgery associated with high blood and volume turnover and intraoperative blood salvage. Serum and bone concentrations and the pharmacokinetics occurring in the context of these procedures were measured. No changes in elimination half-life relative to a normal population occurred with cefuroxime, cefotiam, and ampicillin. Serum and tissue concentrations were slightly lower with cefamandole and sulbactam, but reapplication of the initial dose was required with all antibiotics 4 hours after the first application.

Therapeutic effect of oral levofloxacin, ciprofloxacin, and ampicillin on experimental murine pneumonia caused by penicillin intermediate Streptococcus pneumoniae for which the minimum inhibitory concentrations of the quinolones are similar.

The therapeutic efficacy of oral treatment with levofloxacin, ciprofloxacin, and ampicillin on an experimental pneumonia caused by the penicillin-intermediate Streptococcus pneumoniae for which the minimum inhibitory concentrations (MICs) of the quinolones are similar was assessed in immunocompetent CBA/J mice. Levofloxacin exhibited a dose-dependent therapeutic effect, and achieved complete eradication of S. pneumoniae from the lungs at 120 mg/kg/day, whereas ciprofloxacin and ampicillin were hardly effective at all. A pharmacokinetic study in infected mice revealed good oral absorption and lung tissue penetration of levofloxacin (peak lung concentration: 5.95 microg/g of lung), low oral absorption of ciprofloxacin in spite of a good penetration into lung tissue (1.10 microg/g of lung), and low lung tissue penetration of ampicillin despite rather good oral absorption (1.71 microg/g of lung). In an in vitro time-kill study that simulated the peak concentration of drugs in the lungs of infected animals, the killing activity of levofloxacin was found to be greater than that of ciprofloxacin and ampicillin. These data suggest that the therapeutic efficacy of levofloxacin in this model is attributable to both its potent bactericidal activity and excellent pharmacokinetic profile.

Effect of Khat chewing on the bioavailability of ampicillin and amoxycillin.

The study examined the effect of Khat chewing on ampicillin and amoxycillin bioavailability following the administration of a 500 mg single dose of each antibiotic at different times relative to Khat chewing. Using a urinary excretion method the bioavailabilities of ampicillin and amoxycillin were determined in eight healthy adult male Yemeni volunteers. The extent and rate of ampicillin bioavailability were reduced significantly by Khat chewing except when administered 2 h after the Khat chewing session. However, the bioavailability of amoxycillin was only significantly reduced when the antibiotic was taken midway through the Khat chewing session. It was concluded that the two antibiotics, particularly ampicillin, should be taken 2 h after Khat chewing.

The disposition of five therapeutically important antimicrobial agents in llamas.

The disposition of five therapeutic antimicrobial agents was studied in llamas (Lama glama) following intravenous bolus administration. Six llamas were each given ampicillin, tobramycin, trimethoprim, sulfamethoxazole, enrofloxacin and ceftiofur at a dose of 12 mg/kg, 1 mg/kg, 3 mg/kg, 15 mg/kg, 5 mg/kg, and 2.2 mg/kg of body weight, respectively, with a wash out period of at least 3 days between treatments. Plasma concentrations of these antimicrobial agents over 12 h following i.v. bolus dosing were determined by reverse phase HPLC. Disposition of the five antimicrobial agents was described by a two compartment open model with elimination from the central compartment, and also by non-compartmental methods. From compartmental analysis, the elimination rate constant, half-life, and apparent volume of distribution in the central compartment were determined. Statistical moment theory was used to determine noncompartmental pharmacokinetic parameters of mean residence time, clearance, and volume of distribution at steady state. Based on the disposition parameters determined, and stated assumptions of likely effective minimum inhibitory concentrations (MIC) a dose and dosing interval for each of five antimicrobial agents were suggested as 6 mg/kg every 12 h for ampicillin; 4 mg/kg once a day or 0.75 mg/kg every 8 h for tobramycin; 3.0 mg/kg/15 mg/kg every 12 h for trimethoprim/sulfamethoxazole; 5 mg/kg every 12 h for enrofloxacin; and 2.2 mg/kg every 12 h for ceftiofur sodium for llamas. Steady-state peak and trough plasma concentrations were also predicted for the drugs in this study for llamas.

Antibiotic penetration of experimental intra-abdominal abscesses.

Intra-abdominal abscess is seldom adequately treated by systemic antibiotics alone and often requires surgical or computed tomography-guided drainage for resolution. Abscess penetration of six currently used antibiotics was examined in a murine intra-abdominal abscess model. Ampicillin/sulbactam, cefmetazole, clindamycin, and trospectomycin penetrated intra-abdominal abscesses to a greater degree than cefoxitin and ceftriaxone. Abscess pus antibiotic levels were not significantly higher after multiple doses than after a single dose. Pus antibiotic levels below the MIC90 for Bacteroides and E. coli within intra-abdominal abscess were observed for most antibiotics with the doses used in this study. Selection of antibiotics with a greater ability to penetrate abscess may be important in optimally treating patients with abdominal infection.

[Sulacillin in the treatment of bronchopulmonary diseases]. / Sulatsillin v lechenii bronkholegochnykh zabolevanii.

Antibiotic susceptibility of 279 strains of gram-positive and gram-negative isolates from patients with bronchopulmonary infections was tested. It was shown that the frequency of resistance to ampicillin and sulacillin amounted to 36.5 and 28.8 per cent respectively. The highest clinical efficacy of sulacillin was observed in the treatment of acute pneumonia (good and satisfactory results in 76.2 and 19 per cent of the cases respectively) and chronic nonobstructive bronchitis (good and satisfactory results in 80 and 16 per cent respectively). The clinical efficacy of sulacillin was somewhat lower in the treatment of chronic obstructive bronchitis (good and satisfactory results in 50 and 30 per cent of the cases respectively). In the treatment of chronic purulent bronchitis no clinical effect was detected in 30 per cent of the cases and in 70 per cent of the cases the results were satisfactory. The total frequency of adverse reactions to sulacillin amounted to 18.8 per cent.

Ampicillin/sulbactam in lower respiratory tract infections: a review.

The pathophysiology and microbiology of lower respiratory tract infections are outlined and diagnostic and therapeutic problems considered. The use of sulbactam/ampicillin in the treatment of these infections is evaluated. The two drugs have similar pharmacokinetic characteristics; predictable and dose-dependent peak serum concentrations of both agents are achieved after parenteral administration. More than 90% of strains of Staphylococcus aureus, Haemophilus influenzae, Moraxella catarrhalis, Klebsiella sp, Escherichia coli, and Acinetobacter sp were inhibited by ampicillin/sulbactam concentrations of 16/8 micrograms/ml. Serum concentrations of ampicillin and sulbactam were 18 to 28 micrograms/ml and 13 micrograms/ml, respectively, after intramuscular administration of 1 gm/0.5 gm of ampicillin/sulbactam and 58 micrograms/ml and 30 micrograms/ml, respectively, after intravenous administration of the same dose. Good distribution of ampicillin/sulbactam into lung tissue, sputum, and bronchial fluid has been demonstrated. In over 2,250 patients treated with ampicillin/sulbactam, the rate of discontinuance of treatment because of side effects was less than 1%. Satisfactory clinical and bacteriologic outcome has been reported in over 80% of patients treated with ampicillin/sulbactam. The cost of ampicillin/sulbactam treatment is generally lower than that of other comparable antibiotic regimens.