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O Cars

Publications and source records attributed to O Cars.

At least 19 recordsLinked to original sources
PubMed2005

Pharmacodynamic studies of moxifloxacin and erythromycin against intracellular Legionella pneumophila in an in vitro kinetic model.

BACKGROUND: Newer quinolones are highly active against Legionella pneumophila. Since this pathogen is intracellular, standard in vitro susceptibility tests may not accurately predict clinical efficacy. Few models for studies of intracellular Legionella have been described. In this study, we determined the pharmacodynamic activity of moxifloxacin against intracellular L. pneumophila in comparison with erythromycin. METHODS: A kinetic model for intracellular studies was constructed in which human pharmacokinetics could be simulated. The model consisted of a glass chamber with two exits and a metal rack fitting cell culture inserts. The inserts had a bottom membrane where cells could be cultured while nutrients and antibiotics passed through. The inserts were prepared with a monolayer of HEp-2 cells, which were exposed to a culture of L. pneumophila. At regular intervals cells were harvested and lysed, viable intracellular bacteria counted and compared with untreated controls. RESULTS: The MICs were 0.0156 mg/L for moxifloxacin and 0.5 mg/L for erythromycin. The human pharmacokinetics were simulated in the model with a mean initial antibiotic concentration of 2.4 mg/L for moxifloxacin and 8.4 mg/L for erythromycin. The mean half-life was 9 h for moxifloxacin and 3.4 h for erythromycin. At 12 h, a 2 log(10) reduction in bacterial counts was seen in cells treated with moxifloxacin and no regrowth was detected at 24 h. Cells treated with erythromycin showed no reduction in intracellular L. pneumophilia at 12 h or 24 h. In experiments using static concentrations of 9 mg/L of erythromycin, similar results were obtained. CONCLUSIONS: In this model, moxifloxacin exerts a significantly better antibacterial effect against intracellular L. pneumophila compared with erythromycin.

Aza Compounds↗
PubMed2004

The influence of protein binding on the antibacterial activity of faropenem against Haemophilus influenzae.

The effects of albumin and human serum on the pharmacodynamics of faropenem were studied. The protein binding of faropenem was 91-95%, corresponding to the increase in MICs for Haemophilus influenzae in broth supplemented with albumin. Time-kill experiments in albumin-containing medium and in inactivated human serum 50% v/v showed that much higher drug concentrations were needed to achieve a bactericidal effect than were needed in broth. Active human serum alone exerted a strain-dependent bactericidal effect. It was concluded that it is the free fraction of faropenem in serum that has antibacterial activity against H. influenzae.

Carbapenems↗
PubMed2004

Annual reports of antibiotic use and resistance--for whom?

Sweden, Denmark and the Netherlands, countries with low antibiotic use and low antimicrobial resistance, issue yearly reports on antimicrobial consumption and resistance. In these countries the reports have political priority and aim to disseminate information and promote antibiotic strategies within and between countries.

Annual Reports as Topic↗
PubMed2003

Non-hospital antimicrobial usage and resistance in community-acquired Escherichia coli urinary tract infection.

OBJECTIVES: To investigate the correlation between non-hospital antimicrobial consumption and resistance. METHODS: Information on the non-hospital sales of antimicrobials from 14 European countries in 1997 and 2000 was compared with the antimicrobial resistance profiles of Escherichia coli isolated from women with community-acquired urinary tract infection in the same countries in 1999/2000. RESULTS: There was no statistically significant correlation between the consumption of and resistance to co-amoxiclav, cefadroxil, fosfomycin, mecillinam, sulfamethoxazole, trimethoprim or trimethoprim-sulfamethoxazole. On the other hand, there were statistically significant correlations between consumption of broad-spectrum penicillins and quinolones in 1997 and 2000 and resistance to ciprofloxacin (P range 0.0005-0.0045) and nalidixic acid (P range 0.0013-0.0049). Total antimicrobial consumption in 1997 was significantly correlated to ciprofloxacin (P=0.0009) and nalidixic acid (P=0.0018) resistance, and there were significant relationships between quinolone consumption in both years and resistance to gentamicin (P range 0.0029-0.0043) and nitrofurantoin (P range 0.0003-0.0007). E. coli with multiple antimicrobial resistance were significantly more common in countries with high total antimicrobial consumption. CONCLUSIONS: Owing to the frequent presence of many possible confounding factors, antimicrobial resistance to one drug does not always correlate well to the consumption of the same drug or closely related drugs. This study showed that the degree of antimicrobial consumption was significantly correlated to the incidence of multidrug-resistant E. coli.

Adolescent↗
PubMed2003

In vitro studies of the pharmacodynamics of teicoplanin against Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecium.

OBJECTIVE: To investigate the basic pharmacodynamic properties of teicoplanin in vitro for Staphylococcus aureus, Staphylococcus epidermidis and Enterococcus faecium. METHODS: The following experiments were performed: (1) bacterial killing by teicoplanin at different concentrations; (2) bacterial killing by teicoplanin at 8 x MIC against the same strains with inocula of 5 x 10(3), 5 x 10(5) and 5 x 10(7) CFU/mL; (3) studies of the postantibiotic effect (PAE) and the postantibiotic sub-MIC effect (PASME) of teicoplanin; (4) studies of the killing by teicoplanin in an in vitro kinetic model following exposure to simulated human serum pharmacokinetic concentrations (6 mg/kg OD at steady state). RESULTS: Concentration-dependent killing was noted against S. epidermidis, with a > 4 log10 difference in CFUs between 2 x MIC and 64 x MIC at 24 h. Also, against S. aureus there was slight concentration-dependent killing, which, however, did not reach 2 log10 CFU/mL. Teicoplanin exerted a similar killing rate at all inocula for S. epidermidis, except for slower initial killing up to 6 h at the highest inoculum. In contrast, overall slower killing at all inocula was seen for S. aureus, where an inoculum effect was noted at the highest inoculum. For E. faecium, only a bacteriostatic effect was noted at all concentrations and inocula. No or very short PAEs were noted for the investigated strains. However, when the strains in the postantibiotic phase were exposed to 0.1, 0.2 and 0.3 x MIC of teicoplanin (PASME), substantial prolongation of the PAEs was seen. Although no significant killing was achieved in our kinetic model for any of the strains, regrowth of S. epidermidis was noted first after 8 h, despite a T > MIC24 of only 5% (1.2 h), illustrating the long post-MIC effect for this strain. For S. aureus, T > MIC was 38%, and regrowth occurred later than for S. epidermidis. Neither killing nor regrowth was seen for E. faecium with a T > MIC24 of 27%. CONCLUSION: Teicoplanin exerted a concentration-dependent bactericidal effect against S. epidermidis, a less notable one against S. aureus, and a bacteriostatic effect against E. faecium. A reduced killing rate with increasing inocula was seen for S. aureus and also for S. epidermidis at the highest inoculum. No or very short PAEs were noted for the investigated strains, but were substantially prolonged with the addition of subinhibitory concentrations. When human pharmacokinetics was simulated (6 mg/kg OD at steady state) in the kinetic model, no net bactericidal effect was noted for any of the strains at 24 h.

Anti-Bacterial Agents↗
PubMed2002

Antibiotic prescription practices, consumption and bacterial resistance in a cross section of Swedish intensive care units.

BACKGROUND: The purpose of this work was to study usage of antibiotics, its possible determinants, and patterns of bacterial resistance in Swedish intensive care units (ICUs). METHODS: Prospectively collected data on species and antibiotic resistance of clinical isolates and antibiotic consumption specific to each ICU in 1999 were analyzed together with answers to a questionnaire. Antibiotic usage was measured as defined daily doses per 1000 occupied bed days (DDD1000). RESULTS: Data were obtained for 38 ICUs providing services to a population of approximately 6 million. The median antibiotic consumption was 1257 DDD1000 (range 584-2415) and correlated with the length of stay but not with the illness severity score or the ICU category. Antibiotic consumption was higher in the ICUs lacking bedside devices for hand disinfection (2193 vs. 1214 DDD1000, p=0.05). In the ICUs with a specialist in infectious diseases responsible for antibiotic treatment the consumption pattern was different only for use of glycopeptides (58% lower usage than in other ICUs: 26 vs. 11 DDD1000,P=0.02). Only 21% of the ICUs had a written guideline on the use of antibiotics, 57% received information on antibiotic usage at least every 3 months and 22% received aggregated resistance data annually. Clinically significant antimicrobial resistance was found among Enterbacter spp. to cephalosporins and among Enterococcus spp. to ampicillin. CONCLUSIONS: Availability of hand disinfection equipment at each bed and a specialist in infectious diseases responsible for antibiotic treatment were factors that correlated with lower antibiotic consumption in Swedish ICUs, whereas patient-related factors were not associated with antibiotic usage.

Adult↗
PubMed2002

Pharmacodynamics of amoxicillin/clavulanic acid against Haemophilus influenzae in an in vitro kinetic model: a comparison of different dosage regimens including a pharmacokinetically enhanced formulation.

OBJECTIVE: To study the pharmacodynamics of amoxicillin/clavulanic acid against different strains of Haemophilus influenzae in an in vitro kinetic model. The concentrations used corresponded to human serum levels obtained after 875 mg amoxicillin/clavulanic acid given b.i.d., 500/125 mg amoxicillin/clavulanic acid given t.i.d. and those obtained with a pharmacokinetically enhanced formulation containing 1125/125 mg amoxicillin/clavulanic acid (immediate release) and 875 mg amoxicillin (sustained release) given b.i.d. METHODS: Bacteria at an initial inoculum of 106 colony-forming units (CFU)/mL were exposed to amoxicillin/clavulanic acid with an initial concentration of approximately 15/3 mg/L, 8/3 mg/L simulating the peak levels in humans achieved after a dose of 875/125 mg and 500/125 mg with a half-life of 1 h. In addition, experiments with a 2000/125 mg pharmacokinetically enhanced formulation of amoxicillin/clavulanic acid given b.i.d. were performed. A repeated dose was given at 12 h after the initial dose of 875/125 mg and the pharmacokinetically enhanced formulation or at 8 and 16 h after the dose of 500/125 mg. The experiments were performed in an in vitro kinetic model, which consists of a spinner flask with a filter membrane fitted in between the upper part and the bottom part in order to prevent bacterial dilution. The medium is removed from the culture flask, through the filter, at a constant rate with a pump. Repeated samples were taken at intervals of 1-2 h up to 24 h during the experiments for viable counting. One of the strains of H. influenzae was also exposed to a constant concentration corresponding to the peak serum levels obtained after a dose of 500/125 mg. RESULTS: The concentrations of amoxicillin in the in vitro kinetic model were as expected. At the end of the experiment (24 h), there was a tendency for a greater bactericidal effect with 500/125 mg t.i.d., as compared to 875/125 b.i.d., with differences in CFUs between the two dosing regimens of 2.6 log10 CFU for H. influenzae LH 2803 and 1.8 log10 CFU for the other clinical strains. However, these differences did not reach statistical significance (P = 0.075 and 0.10, respectively). A statistically significant higher bactericidal effect was seen in the experiments with the pharmacokinetically enhanced formulation in comparison with the b.i.d. regimen both at 8, 16 and 24 h and at 8 and 16 h with the t.i.d. regimen. With the new formulation, no regrowth was seen at 24 h, similar to the results obtained with a constant concentration. CONCLUSIONS: Neither of the standard dosing regimens of amoxicillin (875/125 mg b.i.d. or 500/125 mg) used in our study, in which the time that the free (non-protein-bound) concentration the MIC (T > MIC) exceeding was less than 50%, was sufficient to achieve a complete bactericidal effect during the first 24 h of treatment. However, a statistically significant difference in bactericidal activity was seen at 8, 16 and 24 h vs. the b.i.d. regimen and at 8 and 16 h vs. the t.i.d. regimen with the pharmacokinetically enhanced formulation. This formulation gave a longer T > MIC (73-79%) of amoxicillin even though the concentration of clavulanic acid was only detectable for 45% of the dosing interval, and complete killing of all strains was obtained after 24 h.

Amoxicillin↗
PubMed2002

Moving from recommendation to implementation and audit: part 1. Current recommendations and programs: a critical commentary.

Growing concern over the spread of resistance to antibiotics and other antimicrobials has prompted a plethora of recommendations for its control. Strategic programs for resistance containment have been initiated in various countries, particularly in Western Europe and North America. The World Health Organization and the European Union have responded to the need for international action by publishing guidance and encouraging collaboration. These recommendations rightly focus on controlling resistance in the community. They agree on the importance of surveillance of resistance patterns and antibiotic usage and the need to encourage judicious antibiotic usage (especially through education of prescribers and the public). Yet there remains a pressing need for the implementation of effective actions to address these issues. Important considerations given less attention include infection prevention (e.g. through immunization), the use of rapid diagnostic tests to reduce antibiotic usage, audit of implemented actions, and the provision of feedback. Furthermore, research is necessary to fill the substantial gaps in our knowledge. Notably, the reversibility or containment of resistance with the optimization of antibiotic usage has yet to be definitely established. For now, antimicrobial management programs should focus on ensuring the most appropriate use of antimicrobials rather than simply on limiting choices. Finally, developed countries must recognize that a truly global approach to resistance containment will require greater support for developing countries.

Anti-Bacterial Agents↗
PubMed2002

Moving from recommendation to implementation and audit: part 2. Review of interventions and audit.

There are multiple interventions available that may help to control the development and spread of resistance to antimicrobial agents in bacteria implicated in community-acquired respiratory tract infections. Unfortunately, very few studies have assessed the effectiveness of these interventions using objective end-points, such as reduction in resistance rates and improvement in clinical outcomes. Most interventions are centered on reducing inappropriate or unnecessary use of antibiotics; others focus on reducing disease burden and bacterial colonization. With regard to antibiotic use, efforts should be concentrated at both the prescriber and consumer levels. Interventions that target prescribers include: provision of educational materials; strategies and tools to improve diagnosis; implementation of practice guidelines; personalized interactive sessions with feedback on the practice profile; and use of delayed prescription and alternative prescribing strategies. Optimal results are usually obtained when these interventions are combined with consumer education. Regulatory interventions (e.g. licensing regulations and controlled access to drugs), restrictions in the use of agents for growth promotion in animals, and use of nonantimicrobial therapies (e.g. probiotics) may help further to reduce inappropriate antibiotic use and thereby decrease the selective pressure for development of resistance. Infection-control strategies, public health measures, vaccination programs, and new antibiotics all have a role in minimizing the spread of resistant organisms. Ideally, resistance-control programs should include predefined criteria for success and integral audit processes based on objective end-points (antibiotic use, resistance trends, and health outcomes). Standardization of data collection is imperative so that the relative merits of various interventions can be compared. Effective implementation and audit of interventions is often difficult in developing countries owing to poor health-care infrastructures, lack of resources, poor education/training, and minimal regulatory controls on the supply and quality of antimicrobials. Substantial support from governments and health-care organizations across the globe is required to initiate and sustain effective intervention programs to control antimicrobial resistance.

Anti-Bacterial Agents↗
PubMed2002

Antibiotic therapy of community respiratory tract infections: strategies for optimal outcomes and minimized resistance emergence.

Widespread, increasing antibiotic resistance amongst the major respiratory pathogens has compromised traditional therapy of the major infective respiratory syndromes, including bacterial pneumonia and acute exacerbations of chronic bronchitis. Guidelines for antibiotic prescribing dating from the 1980s to 1990s, which attempted to address such problems, were commonly too prescriptive and difficult to apply, and took little account of end-user practice or locally prevalent resistance levels. Further confusion was caused by conflicting recommendations emanating from differing specialty groups. The evidence that such guidelines benefited either clinical outcomes or treatment costs has been disputed. They have probably had little effect on resistance emergence. We report the recommendations of an independent, multi-national, inter-disciplinary group, which met to identify principles underlying prescribing and guideline formulation in an age of increasing bacterial resistance. Unnecessary prescribing was recognized as the major factor in influencing resistance and costs. Antibiotic therapy must be limited to syndromes in which bacterial infection is the predominant cause and should attempt maximal reduction in bacterial load, with the ultimate aim of bacterial eradication. It should be appropriate in type and context of local resistance prevalence, and optimal in dosage for the pathogen(s) involved. Prescribing should be based on pharmacodynamic principles that predict efficacy, bacterial eradication and prevention of resistance emergence. Pharmacoeconomic analyses confirm that bacteriologically more effective antibiotics can reduce overall management costs, particularly with respect to consequential morbidity and hospital admission. Application of these principles should positively benefit therapeutic outcomes, resistance avoidance and management costs and will more accurately guide antibiotic choices by both individuals and formulary/guideline committees.

Community-Acquired Infections↗
PubMed2001

Variation in antibiotic use in the European Union.

Data on antibiotic use are not publicly available in most European Union countries. We obtained data for non-hospital antibiotic sales for 1997 from the 15 member states and analysed these according to the Anatomic Therapeutic Chemical classification system, and expressed them as defined daily doses per 1000 people per day. Sales of antibiotics varied more than four-fold: France (36.5), Spain (32.4), Portugal (28.8), and Belgium (26.7) had the highest sales, whereas the Netherlands (8.9), Denmark (11.3), Sweden (13.5), and Germany (13.6) had the lowest. There was also profound variation in use of different classes of antibiotics. Detailed knowledge of antibiotic use is necessary to implement national strategies for optimum antibiotic use, and to address the threat posed by resistant microorganisms.

Anti-Bacterial Agents↗
PubMed2001

The hidden impact of antibacterial resistance in respiratory tract infection. Steering an appropriate course: principles to guide antibiotic choice.

The prevalence and degree of antibacterial resistance in common respiratory pathogens are increasing worldwide. The health impact of resistance is not yet fully understood. However, once the impact of resistance becomes measurable, it may be too late to apply interventions to reduce resistance levels and regain previous quality and cost of care. We should address resistance now, before patient care is irreversibly compromised. The association between antibiotic consumption and the prevalence of resistance is widely assumed. However, evidence suggests that there is a more complex. multifactorial relationship between antibiotic use and resistance. It is also assumed that there is an adaptive fitness cost for bacterial resistance mutations. However, in some cases, bacteria are able to acquire 'compensatory genes' negating any negative impact of resistance mutations. Mathematical modeling indicates that the timescale for the emergence of resistance is typically shorter than the decay time following a decline in antibiotic consumption. Against this background, a general principle is proposed: to maximize patient outcome whilst minimizing the potential for selection and spread of resistance. This may be achieved through the use of agents that fulfill defined pharmacodynamic and pharmacokinetic parameters and elicit rapid eradication of the bacterial population, including emerging resistant mutants, from the site of infection. The choice of agent may not be the same in all regions, as selection will depend on local resistance patterns and disease etiology; however, the application of this principle may help to preserve the benefits of antibiotic therapy.

Child↗
PubMed2001

Ampicillin-resistant enterococci in a Swedish university hospital: nosocomial spread and risk factors for infection.

Ampicillin-resistant enterococci (ARE) have recently emerged as clinical pathogens in Sweden. Between 1991 and 1995 the incidence of ARE among enterococcal isolates at Uppsala University Hospital increased from 0.5% to 8.1%. Shedding of ARE from infected cases and risk factors for infection with ARE were studied during a period of 7 months for 38 ARE cases and 38 controls with ampicillin-susceptible enterococci. ARE cases had longer mean duration of hospitalization than controls (29 d vs. 15 d; p = 0.002). In univariate analysis other risk factors for infection with ARE were found to be prior therapy with > 2 antimicrobials (odds ratio [OR] 3.3; 95% confidence interval [CI] 1.2-9.5), > 4 weeks of antimicrobial therapy (OR 6.9; CI 1.8-28.3) and cephalosporin therapy (OR 9.1; CI 2.6-33.7). Fourteen of 26 skin carriers of ARE were found to be shedding ARE to the environment, compared to 2 of 12 non-skin carriers (p = 0.03). Pulsed-field gel electrophoresis suggested multifocal origin of the majority of the infecting ARE strains. Non-recognized fecal colonization and silent spread of ARE among many patients and over a prolonged time period is suggested to be the main explanation for the increase of ARE infections in our hospital. Infection control measures focusing on protecting patients at high risk for ARE infections and further efforts to optimize antimicrobial use are proposed.

Ampicillin Resistance↗
PubMed2001

Pharmacodynamics of telithromycin In vitro against respiratory tract pathogens.

Telithromycin (HMR 3647) is a new ketolide that belongs to a new class of semisynthetic 14-membered-ring macrolides which have expanded activity against multidrug-resistant gram-positive bacteria. The aim of the present study was to investigate different basic pharmacodynamic properties of this new compound. The following studies of telithromycin were performed: (i) studies of the rate and extent of killing of respiratory tract pathogens with different susceptibilities to erythromycin and penicillin exposed to a fixed concentration that corresponds to a dose of 800 mg in humans, (ii) studies of the rate and extent of killing of telithromycin at five different concentrations, (iii) studies of the rate and extent of killing of the same pathogens at three different inocula, (iv) studies of the postantibiotic effect and the postantibiotic sub-MIC effect of telithromycin, and (v) determination of the rate and extent of killing of telithromycin in an in vitro kinetic model. In conclusion, telithromycin exerted an extremely fast killing of all strains of Streptococcus pneumoniae both with static concentrations and in the in vitro kinetic model. A slower killing of the strains of Streptococcus pyogenes was noted, with regrowth in the kinetic model of a macrolide-lincosamide-streptogramin B-inducible strain. The strains of Haemophilus influenzae were not killed at all at a concentration of 0.6 mg/liter due to high MICs. A time-dependent killing was seen for all strains. No inoculum effect was seen for the strains of S. pneumoniae, with a 99.9% reduction in the numbers of CFU for all inocula at both 8 h and 24 h. The killing of the strains of S. pyogenes was reduced by 1 log(10) CFU at 8 h and 2 to 3 log(10) CFU at 24 h when the two lower inocula were used but not at all at 8 and 24 h when the highest inoculum was used. For both of the H. influenzae strains there was an inoculum effect, with 1 to 2 log(10) CFU less killing for the inoculum of 10(8) CFU/ml in comparison to that for the inoculum of 10(6) CFU/ml. Overall, telithromycin exhibited long postantibiotic effects and postantibiotic sub-MIC effects for all strains investigated.

Anti-Bacterial Agents↗
PubMed2001

In vitro pharmacodynamic studies of activities of ketolides HMR 3647 (Telithromycin) and HMR 3004 against extracellular or intracellular Helicobacter pylori.

The pharmacodynamic properties of the ketolides HMR 3647 (telithromycin) and HMR 3004 were studied against Helicobacter pylori. Both ketolides showed a pronounced concentration-dependent killing, a significant postantibiotic effect, a long postantibiotic sub-MIC effect, and a reduction of intracellular H. pylori.

Anti-Bacterial Agents↗
PubMed2001

Penicillin pharmacodynamics in four experimental pneumococcal infection models.

Clinical and animal studies indicate that with optimal dosing, penicillin may still be effective against penicillin-nonsusceptible pneumococci (PNSP). The present study examined whether the same strains of penicillin-susceptible pneumococci (PSP) and PNSP differed in their pharmacodynamic responses to penicillin by using comparable penicillin dosing regimens in four animal models: peritonitis, pneumonia, and thigh infection in mice and tissue cage infection in rabbits. Two multidrug-resistant isolates of Streptococcus pneumoniae type 6B were used, one for which the penicillin MIC was 0.016 microg/ml and the other for which the penicillin MIC was 1.0 microg/ml. Two additional strains of PNSP were studied in the rabbit. The animals were treated with five different penicillin regimens resulting in different maximum concentrations of drugs in serum (C(max)s) and times that the concentrations were greater than the MIC (T(>MIC)s). The endpoints were bacterial viability counts after 6 h of treatment in the mice and 24 h of treatment in the rabbits. Similar pharmacodynamic effects were observed in all models. In the mouse models bactericidal activity depended on the T(>MIC) and to a lesser extent on the Cmax/MIC and the generation time but not on the area under the concentration-time curve (AUC)/MIC. Maximal bactericidal activities were similar for both PSP and PNSP, being the highest in the peritoneum and blood (approximately 6 log10 CFU/ml), followed by the thigh (approximately 3 log10 CFU/thigh), and being the lowest in the lung (approximately 1 log10 CFU/lung). In the rabbit model the maximal effect was approximately 6 log10 CFU/ml after 24 h. In the mouse models bactericidal activity became marked when T(>MIC) was > or =65% of the experimental time and C(max) was > or =15 times the MIC, and in the rabbit model bactericidal activity became marked when T(>MIC) was > or =35%, Cmax was > or =5 times the MIC, and the AUC at 24 h/MIC exceeded 25. By optimization of the Cmax/MIC ratio and T(>MIC), the MIC of penicillin for pneumococci can be used to guide therapy and maximize therapeutic efficacy in nonmeningeal infections caused by PNSP.

Animals↗
PubMed2001

Pharmacokinetic and pharmacodynamic parameters for antimicrobial effects of cefotaxime and amoxicillin in an in vitro kinetic model.

An in vitro kinetic model was used to study the relation between pharmacokinetic and pharmacodynamic (PK-PD) parameters for antimicrobial effect, e.g., the time above MIC (T>MIC), maximum concentration in serum (C(max)), and area under the concentration-time curve (AUC). Streptococcus pyogenes and Escherichia coli were exposed to cefotaxime, and the activity of amoxicillin against four strains of Streptococcus pneumoniae with different susceptibilities to penicillin was studied. The drug elimination rate varied so that the T>MIC ranged from 20 to 100% during 24 h, while the AUC and/or the initial concentration (C(max)) were kept constant. For S. pyogenes and E. coli, the maximal antimicrobial effect (E(max)) at 24 h occurred when the antimicrobial concentration exceeded the MIC for 50 and 80% of the strains tested, respectively. The penicillin-susceptible pneumococci (MIC, 0.03 mg/liter) and the penicillin-intermediate strain (MIC, 0.25 mg/liter) showed maximal killing by amoxicillin at a T>MIC of 50%. For a strain for which the MIC was 2 mg/liter, C(max) needed to be increased to achieve the E(max). Under the condition that C(max) was 10 times the MIC, E(max) was obtained at a T>MIC of 60%, indicating that C(max), in addition to T>MIC, may be an important parameter for antimicrobial effect on moderately penicillin-resistant pneumococci. For the strain for which the MIC was 4 mg/liter, the reduction of bacteria varied from -0.4 to -3.6 log(10) CFU/ml at a T>MIC of 100%, despite an initial antimicrobial concentration of 10 times the MIC. Our studies have shown that the in vitro kinetic model is a useful complement to animal models for studying the PK-PD relationship for antimicrobial effect of antibiotics.

Amoxicillin↗