Population pharmacokinetics and pharmacodynamics of piperacillin/tazobactam in patients with complicated intra-abdominal infection.

OBJECTIVES: We investigated the population pharmacokinetics and pharmacodynamics of piperacillin and tazobactam in hospitalized patients. PATIENTS AND METHODS: A multicentre, randomized clinical trial was conducted in hospitalized patients with complicated intra-abdominal infection. Patients received piperacillin/tazobactam administered by either continuous infusion (13.5 g over 24 h, n = 130) or intermittent infusion (3.375 g every 6 h, n = 132). NONMEM was used to perform population pharmacokinetic analysis in a subset of patients (n = 56) who had serum samples obtained at steady-state for drug concentration analyses. Classification and regression tree analysis was used to identify the breakpoints of piperacillin PK-PD indexes in 94 patients with causative pathogen's MIC. RESULTS: A one-compartment model was applied to fit the data. Creatinine clearance and body weight were the most significant variables to explain patient variability in piperacillin and tazobactam clearance and volume of distribution. The infusion method had no influence on PK parameters. For patients (n = 30) receiving intermittent infusion in the pharmacokinetic study, mean Cmax and half-life were 122.22 mg/L and 1.17 h for piperacillin, and 15.74 mg/L and 1.81 h for tazobactam. For patients (n = 26) receiving continuous infusion in the pharmacokinetic study, mean steady-state concentration was 35.31 +/- 12.15 mg/L for piperacillin and 7.29 +/- 3.28 mg/L for tazobactam. As a result of a low rate of failures (<11%) observed in the trial and the low MICs for infecting pathogens, no association could be established between clinical/microbiological outcome and drug exposure. CONCLUSIONS: Intermittent infusion and continuous infusion of piperacillin and tazobactam provided sufficient drug exposure to treat those pathogens commonly implicated in intra-abdominal infections.

Effect of opsonophagocytosis mediated by specific antibodies on the co-amoxiclav serum bactericidal activity against Streptococcus pneumoniae after administration of a single oral dose of pharmacokinetically enhanced 2000/125 mg co-amoxiclav to healthy volunteers.

OBJECTIVES: To measure the effect of opsonophagocytosis mediated by complement activated by specific antibodies on the co-amoxiclav serum bactericidal activity against Streptococcus pneumoniae strains with reduced susceptibility to beta-lactams (amoxicillin MICs of 2, 4, 8 and 16 mg/L). METHODS: An open Phase I study measuring ex vivo bactericidal activity after anti-pneumococcal vaccination and an oral dose of 2000/125 mg sustained-release co-amoxiclav was carried out. The ex vivo bactericidal activity was investigated through killing curves over 3 h [assuring polymorphonuclear neutrophil (PMN) viability] with serum samples collected 1.5 h and 5 h after dosing. Global killing was measured as the area under the killing curve (AUKC; log cfu x h/mL). The AUKC of the control growth curve of S. pneumoniae in Hanks' balanced salt solution (AUKC(K)) was used as control. The effect of the presence of complement and/or PMN was evaluated by the difference in the AUKC(K) and the different AUKCs obtained in the presence of inactivated serum (AUKC(IS)), active serum (AUKC(S)), inactivated serum plus PMN (AUKC(IS+PMN)) and active serum plus PMN (AUKC(S+PMN)). RESULTS: Significant differences were found in all cases between the bactericidal activity of active serum+PMN (AUKC(K) - AUKC(S+PMN)) and that of inactivated serum (AUKC(K) - AUKC(IS)) with therapeutic indexes ranging from 0.56 to 3.04. At 1.5 h after dosing, a significantly higher bactericidal activity of co-amoxiclav was obtained when opsonophagocytosis occurred (samples with active serum and PMN) than when not occurring (killing curves with inactivated serum and without PMN), for all amoxicillin non-susceptible strains. CONCLUSIONS: The results of this ex vivo study suggest that the collaboration of co-amoxiclav and complement-mediated opsonophagocytosis activated by specific antibodies may lay new approaches to overcome in vivo amoxicillin non-susceptibility.

[Pharmacokinetic/pharmacodynamic analysis of antibiotic therapy in dentistry and stomatology]. / Análisis farmacocinético/farmacodinámico (PK/PD) de la antibioterapia en odontoestomatología.

INTRODUCTION: This study evaluates the efficacy of various antimicrobial treatments for orofacial infections on the basis of pharmacokinetic/pharmacodynamic (PK/PD) criteria. METHODS: A complete a literature search was undertaken to establish the MIC90 values of the five microorganisms most frequently isolated in odontogenic infections and the pharmacokinetic parameters of 13 antibiotics used in these infections. Pharmacokinetic simulations were then carried out with mean population parameters and efficacy indexes were calculated for the 47 treatment regimens analyzed. For drugs showing time-dependent antibacterial killing, the time above MIC (t > MIC) was calculated. For drugs with concentration-dependent bactericidal activity, the AUC/MIC was calculated. RESULTS: Amoxicillin-clavulanic (500 mg/8 h or 1000 mg/12 h) and clindamycin (300 mg/6 h) in the time-dependent killing group and moxifloxacin (400 mg/24 h) in the concentration-dependent group showed adequate efficacy indexes against the five pathogens considered to be the most commonly implicated in odontogenic infections. The spiramycin plus metronidazole combination, present in the commercial formulation Rhodogyl, did not reach satisfactory PK/PD indexes. CONCLUSION: PK/PD indexes, which are useful predictors of the potential efficacy of antibacterial therapy, were used with ontogenic infections in the present study. The PK/PD simulations showed that amoxicillin-clavulanic, clindamycin and moxifloxacin were the most suitable antibiotics for this kind of infection. Clinical trials are required to confirm that this methodology is useful in these pathologic processes.

Pharmacodynamic studies of amoxicillin against Streptococcus pneumoniae: comparison of a new pharmacokinetically enhanced formulation (2000 mg twice daily) with standard dosage regimens.

OBJECTIVES: To compare the pharmacodynamic effects of a pharmacokinetically enhanced formulation of amoxicillin 2000 mg twice daily, with amoxicillin 875 mg twice daily, 875 mg three times daily and 500 mg three times daily against Streptococcus pneumoniae with different susceptibility to amoxicillin in an in vitro kinetic model. METHODS: Strains of S. pneumoniae with amoxicillin MICs of 1, 2, 4 and 8 mg/L at an initial inoculum of approximately 10(5) cfu/mL were exposed to amoxicillin in an in vitro kinetic model simulating the human serum concentration-time profile of the pharmacokinetically enhanced formulation twice daily (C(max) 17 mg/L after 1.5 h). All isolates were also exposed to amoxicillin with concentration-time profiles correlating to the human dosage of 875 mg twice daily (C(max) 15 mg/L after 1 h), 875 mg three times daily and 500 mg (C(max) 8 mg/L after 1 h) three times daily with simulated half-life of 1 h. Repeated samples were taken regularly during 24 h and viable counts were carried out. RESULTS: Overall, the pharmacokinetically enhanced formulation was more effective at reducing bacterial counts than any of the other formulations evaluated. Eradication was achieved with the enhanced formulation for strains with a MIC of < or =2 mg/L, however, regrowth occurred with the other dosing regimens. In the experiments with the strain with a MIC of 4 mg/L, the enhanced formulation kept the bacterial counts < or =10(2) cfu/mL for at least 14 out of 24 h tested. In contrast, none of the other formulations reduced the bacterial counts down to < or =10(2) cfu/mL at any point. None of the regimens was able to eradicate the strain with an MIC of 8 mg/L, even though an initial substantial kill was noted with the enhanced formulation after both doses. The least effective dosage regimen for all strains was 875 mg twice daily.

Bioequivalence evaluation of two brands of amoxicillin/clavulanic acid 250/125 mg combination tablets in healthy human volunteers: use of replicate design approach.

The purpose of this study was to apply a replicate design approach to a bioequivalence study of amoxicillin/clavulanic acid combination following a 250/125 mg oral dose to 23 subjects, and to compare the analysis of individual bioequivalence with average bioequivalence. This was conducted as a 2-treatment 2-sequence 4-period crossover study. Average bioequivalence was shown, while the results from the individual bioequivalence approach had no success in showing bioequivalence. In conclusion, the individual bioequivalence approach is a strong statistical tool to test for intra-subject variances and also subject-by-formulation interaction variance compared with the average bioequivalence approach.

Effect of the formulation on the bioequivalence of sultamicillin: tablets and suspension.

Sultamicillin (CAS 76497-13-7) is a pro-drug of a combination of ampicillin and sulbactam linked as a double ester. The aim of the present studies, performed in two different groups of volunteers, was to compare the bioavailability of 750 mg sultamicillin tablets (Duobaktam 750 mg tablets, study 1) and sultamicillin 250 mg/5mL suspensions (Duobaktam 250 mg/5mL, study 2). Each study was conducted according to an open, randomized, single-dose, two-period cross-over design in 24 healthy volunteers with a wash-out period from 7 to 14 days. Blood samples were taken up to 12 h post dosing, and concentrations of ampicillin and sulbactam were determined by a HPLC-UV method. In the first study, the 90% confidence interval for intra-individual ratios of AUC0-t and Cmax of ampicillin and sulbactam were between 1.01-1.18 and 0.95-1.09 (AUC0-t) as well as between 0.87-1.04 and 0.80-0.96 (Cmax), respectively, and thus within the acceptance ranges. The 90% confidence interval for intra-individual ratios of AUC0-t and Cmax of sultamicillin suspensions (2nd study) were between 0.94-1.16 (ampicillin) and 0.92-1.14 (sulbactam) for AUC0-t and between 0.96-1.23 (ampicillin) and 0.97-1.24 (sulbactam) for Cmax. These values were also within the acceptance range for bioequivalence studies. Concerning the secondary parameter tmax the 90%-confidence interval for the intra-individual differences for both ampicillin and sulbactam were between 0.00-0.50 in the first and between -0.17-0.00 in the second study, respectively. In the light of the present studies it can be concluded that the sultamicillin test formulations, i.e. tablet and suspension are bioequivalent to the respective reference formulations.

[Optimization of amoxicillin/clavulanate therapy based on pharmacokinetic/pharmacodynamic parameters in patients with diabetic foot infection]. / Optimalizace lécby amoxicilín/klavulanátem na základe PK/PD parametru u nemocných s infekcí pri syndromu diabetické nohy.

AIM OF THE STUDY: Individualized optimization of amoxicillin/clavulanate (AMC) antimicrobial therapy in diabetic foot infection. METHODS: Pharmacokinetic analysis of individual steady-state plasma amoxicillin concentrations was done both in the i.v. infusion phase and in the oral phase of AMC, administered on the basis of the quantitative susceptibility of the detected microbe(s). The in vitro growth/killing dynamic parameters on model of Staphylococcus aureus as the most frequent isolate were evaluated. Therapeutic protocol optimization, leading to prediction of the earliest time to reduce the number of viable bacteria to 10-6 as a surrogate criterion of efficacy, was performed. RESULTS: Based on individual plasma amoxicillin oscillations in 17 patients suffering from infected diabetic foot ulcers and the model microbial dynamic parameters, the reduction of the number of viable bacteria was reached significantly earlier after the administration of continuous i.v. AMC infusion than after the same daily AMC dose administered intermittently. In case of highly susceptible staphylococcal strain, highly frequent oral therapy of AMC (not longer than 8 hrs dosing interval) was also sufficiently effective. Decreasing plasma amoxicillin concentrations exponentially extended the time required for effective reduction of microbes. CONCLUSION: Individualized optimization of amoxicillin/clavulanate dosage on the basis of growth/killing microbial dynamic parameters and antibiotic concentration/time fluctuations may enhance the antimicrobial effect and the treatment of infected non-critical ischemic diabetic foot ulcers.

Double-blind, randomized study of the efficacy and safety of oral pharmacokinetically enhanced amoxicillin-clavulanate (2,000/125 milligrams) versus those of amoxicillin-clavulanate (875/125 milligrams), both given twice daily for 7 days, in treatment of bacterial community-acquired pneumonia in adults.

This randomized, double-blind, noninferiority trial was designed to demonstrate that pharmacokinetically enhanced amoxicillin-clavulanate (2,000/125 mg) was at least as effective clinically as amoxicillin-clavulanate 875/125 mg, both given twice daily for 7 days, in the treatment of community-acquired pneumonia in adults. In total, 633 clinically and radiologically confirmed community-acquired pneumonia patients (intent-to-treat population) were randomized to receive either oral amoxicillin-clavulanate 2,000/125 mg (n = 322) or oral amoxicillin-clavulanate 875/125 mg (n = 311). At screening, 160 of 633 (25.3%) patients had at least one typical pathogen isolated from expectorated or invasive sputum samples or blood culture (bacteriology intent-to-treat population). Streptococcus pneumoniae (58 of 160, 36.3%), methicillin-susceptible Staphylococcus aureus (34 of 160, 21.3%), and Haemophilus influenzae (33 of 160, 20.6%) were the most common typical causative pathogens isolated in both groups in the bacteriology intent-to-treat population. Clinical success in the clinical per protocol population at test of cure (days 16 to 37), the primary efficacy endpoint, was 90.3% (223 of 247) for amoxicillin-clavulanate 2,000/125 mg and 87.6% (198 of 226) for amoxicillin-clavulanate 875/125 mg (treatment difference, 2.7; 95% confidence interval, -3.0, 8.3). Bacteriological success at test of cure in the bacteriology per protocol population was 86.6% (58 of 67) for amoxicillin-clavulanate 2,000/125 mg and 78.4% (40 of 51) for amoxicillin-clavulanate 875/125 mg (treatment difference, 8.1%; 95% confidence interval, -5.8, 22.1). Both therapies were well tolerated. Amoxicillin-clavulanate 2,000/125 mg twice daily was shown to be as clinically effective as amoxicillin-clavulanate 875/125 mg twice daily for 7 days in the treatment of adult patients with community-acquired pneumonia, without a noted increase in the reported rate of adverse events.

Antibacterial effects of amoxicillin-clavulanate against Streptococcus pneumoniae and Haemophilus influenzae strains for which MICs are high, in an in vitro pharmacokinetic model.

The antibacterial effect of amoxicillin-clavulanate in two formulations, pharmacokinetically enhanced 16:1 amoxicillin-clavulanate twice a day (b.i.d.) and standard 7:1 amoxicillin-clavulanate b.i.d., were studied in an in vitro pharmacokinetic model of infection. Five strains of Streptococcus pneumoniae and two of Haemophilus influenzae, all associated with raised MICs (2 to 8 mg/liter), were used. The antibacterial effect was measured over 24 h by the area under the bacterial kill curve (AUBKC) and the log change in viable count at 24 h (Delta24). A high 10(8) CFU/ml and low 10(6) CFU/ml initial inocula were used. Employing the Delta24 effect measure, the time above MIC (T>MIC) 50% maximum effect (EC(50)) for S. pneumoniae was in the range 21 to 28% with an 80% maximal response of 41 to 51%, for the AUBKC measure, the value was 26 to 39%, irrespective of inoculum. For H. influenzae, the T>MIC EC(50) was 28 to 37%, and the 80% maximum response was 32 to 48% for the Delta24 measure and 20 to 48% for AUBKC. The maximum response occurred at a T>MIC of 50 to 60% for both species and inocula. The S. pneumoniae data were analyzed by analysis of variance to assess the effect of inoculum, formulation, and MIC on antibacterial effect. Standard and enhanced formulations had different effects depending on MIC, with the standard formulation less effective at higher amoxicillin-clavulanate MICs. This is explained by the greater T>MICs of the enhanced formulation. Although resistant to amoxicillin-clavulanate by conventional breakpoints, S. pneumoniae and H. influenzae strains for which MICs are 2 or 4 mg/liter may well respond to therapy with pharmacokinetically enhanced formulation amoxicillin-clavulanate.

Effect of antibiotic sequence on combination regimens against Pseudomonas aeruginosa in a multiple-dose, in vitro infection model.

The goal of this study was to investigate the effect of antibiotic sequence on combination regimens against Pseudomonas aeruginosa in an in vitro infection model. Ceftazidime plus ciprofloxacin and ceftazidime plus tobramycin were dosed every 12 h for 48 h using simultaneous or staggered administration. Simultaneous dosing and ceftazidime followed by ciprofloxacin or tobramycin were significantly more active at both 24 h (p = 0.03) and 48 h (p < 0.0001) than ciprofloxacin or tobramycin followed by ceftazidime. Final bacterial kill was sixfold greater with the former regimens. This study showed that antibiotic sequence had a significant and class dependent effect on antibacterial response. The clinical relevance of these observations warrants further investigations in animal models.

Evaluation of a triple-drug combination for treatment of experimental multidrug-resistant pneumococcal meningitis.

To evaluate the therapeutic efficacy of ceftriaxone + vancomycin + rifampicin (CVR) in the treatment of pneumococcal meningitis caused by a multidrug-resistant strain, single-drug regimens (ceftriaxone 100 mg/kg, rifampicin 15 mg/kg, or vancomycin 20 mg/kg), double-drug regimens (ceftriaxone + vancomycin [CV] and ceftriaxone + rifampicin [CR]) and a triple-drug combination (CVR) with or without dexamethasone were compared in a rabbit meningitis model. Meningitis was induced by a highly penicillin-resistant (MIC 2 mg/l) and ceftriaxone-resistant (MIC 4 mg/l) pneumococcal strain. Final therapeutic efficacy was evaluated by the bacterial concentration at 24 h, and the bacterial killing rate was also evaluated. All combination regimens were superior to ceftriaxone or vancomycin single-drug regimens with regard to sterilisation of CSF and bacterial killing rate. Rifampicin was as effective as combination regimens. Regardless of dexamethasone, therapeutic efficacy of CVR and CR were superior to that of CV. CVR showed comparable therapeutic efficacy to CR. Data suggested that CVR would not have additional therapeutic benefit over CR during the initial 24 h of treatment.

Amoxicillin/clavulanic acid (875/125): bioequivalence of a novel Solutab tablet and rationale for a twice-daily dosing regimen.

A new amoxicillin/clavulanic acid tablet formulation (Solutab tablet, Forcid Solutab) containing amoxicillin/clavulanic acid (875/125) has been developed. The aim of the present study was to demonstrate bioequivalence between the new tablet formulation (test), taken as an intact tablet and after prior dispersal, versus the originator product viz. Augmentan film-coated tablet (875/125) used as reference. The study was performed in 48 healthy volunteers according to an open, single-dose, crossover design. Bioequivalence was demonstrated using Cmax and AUC(0-infinity) as primary parameters of evaluation for both amoxicillin and clavulanic acid with 90% confidence intervals of the ratios Solutab tablet/Augmentan within the range of 0.8-1.25. The duration of the plasma concentration exceeding the amoxicillin minimal inhibitory concentration (MICs) was calculated using individual plasma concentration-time curves and compartmental analysis. The data showed that the bioavailability characteristics of the test tablet, taken intact or in dispersed form, and the reference tablets were very similar. The analysis, moreover, also confirmed the appropriateness of using a b.i.d. dosage regimen for both formulations, taking into account the pharmacodynamic breakpoint values for some major pathogens.

Pharmacokinetic and pharmacodynamic issues in the treatment of bacterial infectious diseases.

This review outlines some of the many factors a clinician must consider when selecting an antimicrobial dosing regimen for the treatment of infection. Integration of the principles of antimicrobial pharmacology and the pharmacokinetic parameters of an individual patient provides the most comprehensive assessment of the interactions between pathogen, host, and antibiotic. For each class of agent, appreciation of the different approaches to maximize microbial killing will allow for optimal clinical efficacy and reduction in risk of development of resistance while avoiding excessive exposure and minimizing risk of toxicity. Disease states with special considerations for antimicrobial use are reviewed, as are situations in which pathophysiologic changes may alter the pharmacokinetic handling of antimicrobial agents.

Specific antibiotics in the treatment of periodontitis--a proposed strategy.

BACKGROUND: The purpose of the present study was to propose a strategy for the selection of antibiotics that specifically target complexes of periodontal pathogens present in patients with periodontitis. METHODS: Seven hundred seventy-four (774) patients with various forms of periodontitis were included in the study. Subgingival plaque samples were taken from the deepest periodontal pockets in each quadrant using a sterile curet, and pooled. Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis, Eikenella corrodens, Tannerella forsythensis, Prevotella intermedia, and Prevotella nigrescens were identified by polymerase chain reaction, and the prevalence of combinations of these pathogens was determined. To each pathogen complex (PC), i.e., combination of pathogens, those antibiotics were assigned that were most specific according to the published minimum inhibitory concentration (MIC90) values and the gingival crevicular fluid (GCF) concentrations achievable in vivo. Antibiotic GCF concentrations had to be at least 10 times the MIC90 values, and the narrowest spectrum was selected with respect to the assessed periodontal pathogens. RESULTS: Nine major PCs (each > or = 3% of all patients) were found in 73.4% of all patients, whereas 38 minor PCs (each < 3% of all patients) were distributed in 26.6% of all patients. Ten different antibiotic regimens were found to be specific for the total of 46 PCs; i.e., metronidazole and amoxicillin in 11 PCs (55.0% of all patients), metronidazole and amoxicillin/clavulanic acid or metronidazole and ciprofloxacin in 13 PCs (18.9%), amoxicillin in 4 PCs (8.3%), doxycycline in 2 PCs (6.1%), metronidazole in 8 PCs (4.1%), amoxicillin/clavulanic acid in 3 PCs (2.9%), clindamycin in 2 PCs (1.5%), ciprofloxacin in 2 PCs (0.4%), and tetracycline in 1 PC (0.3%). CONCLUSION: The results of the study indicate that there are at least 46 different combinations of the assessed periodontal pathogens in subjects with periodontitis, and at least 10 different antibiotic regimens might be required to specifically target the various pathogen complexes.

Elements of design: the knowledge on which we build.

The time the free drug serum concentration of antibiotic remains above the pathogen MIC (T > MIC) determines bacteriological efficacy and emergence or selection of resistance for penicillin and amoxicillin with or without clavulanate. Multiple studies in animal and in-vitro models now support this conclusion. The size of the T > MIC (the pharmacokinetic/-dynamic target) is > 40-50% to maximise antibacterial effect and pathogen eradication for Streptococcus pneumoniae and probably also Haemophilus influenzae. The size of the T > MIC for optimal antibacterial effect is changed by host immune status but not by bacterial inoculum or mechanism of resistance. There is good animal evidence to support the prediction that, as long as the target T > MIC is achieved, strains of S. pneumoniae with amoxicillin MICs of 0.016 mg/L will respond to amoxicillin in the same way as those with MICs of 1-2 mg/L. Emergence of resistance to amoxicillin/clavulanate in S. pneumoniae is related to low T > MIC (< 20%) and also to the degree of population heterogeneity to amoxicillin. Selection of resistant strains of S. pneumoniae is also related to T > MIC. Monte Carlo simulations based on the pharmacokinetics of amoxicillin with or without clavulanate in humans are needed to best predict the likely efficacy of different amoxicillin dosing regimens. This approach adequately allows the considerable pharmacokinetic variability in amoxicillin handling by infected patients to be accounted for as well as differences in pathogen beta-lactam susceptibility.

Augmentin (amoxicillin/clavulanate) in the treatment of community-acquired respiratory tract infection: a review of the continuing development of an innovative antimicrobial agent.

Amoxicillin/clavulanate (Augmentin) is a broad-spectrum antibacterial that has been available for clinical use in a wide range of indications for over 20 years and is now used primarily in the treatment of community-acquired respiratory tract infections. Amoxicillin/clavulanate was developed to provide a potent broad spectrum of antibacterial activity, coverage of beta-lactamase-producing pathogens and a favourable pharmacokinetic/pharmacodynamic (PK/PD) profile. These factors have contributed to the high bacteriological and clinical efficacy of amoxicillin/clavulanate in respiratory tract infection over more than 20 years. This is against a background of increasing prevalence of antimicrobial resistance, notably the continued spread of beta-lactamase-mediated resistance in Haemophilus influenzae and Moraxella catarrhalis, and penicillin, macrolide and quinolone resistance in Streptococcus pneumoniae. The low propensity of amoxicillin/clavulanate to select resistance mutations as well as a favourable PK/PD profile predictive of high bacteriological efficacy may account for the longevity of this combination in clinical use. However, in certain defined geographical areas, the emergence of S. pneumoniae strains with elevated penicillin MICs has been observed. In order to meet the need to treat drug-resistant S. pneumoniae, two new high-dose amoxicillin/clavulanate formulations have been developed. A pharmacokinetically enhanced tablet dosage form of amoxicillin/clavulanate 2000/125 mg twice daily (available as Augmentin XR in the USA), has been developed for use in adult respiratory tract infection due to drug-resistant pathogens, such as S. pneumoniae with reduced susceptibility to penicillin, as well as beta-lactamase-producing H. influenzae and M. catarrhalis. Amoxicillin/clavulanate 90/6.4 mg/kg/day in two divided doses (Augmentin ES-600) is for paediatric use in persistent or recurrent acute otitis media where there are risk factors for the involvement of beta-lactamase-producing strains or S. pneumoniae with reduced penicillin susceptibility. In addition to high efficacy, amoxicillin/clavulanate has a well known safety and tolerance profile of the two new high-dose formulations are not significantly different from those of conventional formulations. Amoxicillin/clavulanate is included in guidelines and recommendations for the treatment of bacterial sinusitis, acute otitis media, community-acquired pneumonia and acute exacerbations of chronic bronchitis. Amoxicillin/clavulanate continues to be an important agent in the treatment of community-acquired respiratory tract infections, both now and in the future.

Release of gentamicin and vancomycin from temporary human hip spacers in two-stage revision of infected arthroplasty.

AIM: Evaluation of the delivery of gentamicin and vancomycin from polymethylmethacrylate (PMMA) spacers before and after implantation for the treatment of total hip replacement infections. METHODS: Twenty industrially produced spacers containing gentamicin (1.9%) were utilized. Vancomycin (2.5%) mixed with PMMA cement was used to fill holes drilled in the cement of 14 of the 20 spacers immediately before implantation. The spacers were removed from 20 patients 3-6 months after implantation and then immersed in phosphate buffer at 37 degrees C for 10 days. Antibiotic concentrations were determined by fluorescence polarization immunoassay. RESULTS: Gentamicin and vancomycin were still present in all the spacers removed from the patients. The release of gentamicin alone and in combination with vancomycin was in the range 0.05%-0.4% of the initial amount present, whereas the release of vancomycin was in the range 0.8%-3.3%. The release kinetics showed a similar pattern for both drugs. After a high initial release of drug, a reduced, but constant, elution was observed over the next few days. CONCLUSIONS: The delivery of gentamicin and vancomycin from PMMA cement was high initially, with sustained release over several months. Incorporation of vancomycin into the surface of the spacers permitted spacers to be prepared with multiple antibiotics present and without adversely affecting the release kinetics of the agents. The gentamicin-vancomycin combination shows potential for the treatment of infection following total hip replacement in specific patients.

Pharmacokinetics of a combination preparation of ampicillin and sulbactam in turkeys.

OBJECTIVE: To investigate the disposition kinetics of ampicillin and sulbactam after IV and IM administration of an ampicillin-sulbactam (2:1) preparation and determine the bioavailability of the combined preparation after IM administration in turkeys. ANIMALS: 10 healthy large white turkeys. PROCEDURE: In a crossover study, turkeys were administered the combined preparation IV (20 mg/kg) and IM (30 mg/kg). Blood samples were collected before and at intervals after drug administrations. Plasma ampicillin and sulbactam concentrations were measured by use of high-performance liquid chromatography; plasma concentration-time curves were analyzed via compartmental pharmacokinetics and noncompartmental methods. RESULTS: The drugs were distributed according to an open 2-compartment model after IV administration and a 1-compartment model (first-order absorption) after IM administration. For ampicillin and sulbactam, the apparent volumes of distribution were 0.75+/-0.11 L/kg and 0.74+/-0.10 L/kg, respectively, and the total body clearances were 0.67+/-0.07 L x kg(-1) x h(-1) and 0.56+/-0.06 L x kg(-1) x h(-), respectively. The elimination half-lives of ampicillin after IV and IM administration were 0.78+/-0.12 hours and 0.89+/-0.17 hours, respectively, whereas the corresponding half-lives of sulbactam were 0.91+/-0.12 hours and 0.99+/-0.16 hours, respectively. Bioavailability after IM injection was 58.87+/-765% for ampicillin and 53.75+/-5.35% for sulbactam. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that a regimen of loading and maintenance doses of 300 mg of the ampicillin-sulbactam (2:1) combination/kg every 8 hours could be clinically useful in turkeys. This dosage regimen maintained plasma concentrations of ampicillin > 0.45 microg/mL in turkeys.

Amoxicillin/clavulanate for infections in infants and children: past, present and future.

Chemical synthesis of the penicillin nucleus in the 1950s made introduction of a broad array of new and important antimicrobials, including ampicillin and amoxicillin, possible. Ampicillin was introduced in 1962 in oral and parenteral forms as the first of the semisynthetic penicillins to provide increased activity against Gram-negative bacteria. Amoxicillin replaced oral ampicillin beginning in 1974 because amoxicillin resulted in higher and more prolonged serum concentrations than did equivalent doses of ampicillin. Amoxicillin/clavulanate (Augmentin) was introduced in the United States in 1984 to enhance the activity of amoxicillin by addition of the beta-lactamase inhibitor, clavulanic acid. During the past 20 years, amoxicillin/clavulanate has proven effective for a variety of pediatric infectious diseases, particularly acute otitis media (AOM). In 2001, a new pediatric formulation, high dose amoxicillin/clavulanate (Augmentin ES-600) was approved for use in the United States. The high dose preparation addressed the needs of pediatricians by providing greater amounts of amoxicillin while maintaining the same daily dose of clavulanic acid as the regular strength formulation. Doubling the dose of amoxicillin for management of recurrent and persistent AOM was recommended in 1999 by the Centers for Disease Control and Prevention because of concern about the increased incidence of nonsusceptible strains of Streptococcus pneumoniae. The original formulation combined amoxicillin/clavulanate in a 4:1 ratio and was followed by a 7:1 ratio formulation. The high dose formulation (600 mg of amoxicillin per 5 ml) provides a 14:1 ratio of amoxicillin to clavulanate. Although management of AOM will likely undergo changes in the coming years, amoxicillin is expected to remain first line therapy for AOM. For children who fail initial therapy with amoxicillin, high dose amoxicillin/clavulanate, an oral cephalosporin or parenteral ceftriaxone is recommended.