Pharmacodynamic studies of nitrofurantoin against common uropathogens.

OBJECTIVES: To determine the pharmacokinetic/pharmacodynamic index that best correlates to nitrofurantoin's antibacterial effect, we studied nitrofurantoin activity against common causative pathogens in uncomplicated urinary tract infection (UTI). METHODS: Five isolates [two Escherichia coli (one isolate producing the ESBL CTX-M-15), two Enterococcus faecium (including one that was vancomycin resistant) and one Staphylococcus saprophyticus] were used. The MICs of nitrofurantoin were determined by Etest. Time-kill curves with different concentrations of nitrofurantoin (based on multiples of isolate-specific MICs) were followed over 24 h. An in vitro kinetic model was used to simulate different time-concentration profiles, exposing E. coli to nitrofurantoin for varying proportions of the dosing interval. The outcome parameters reduction in cfu 0-24 h (Δcfu0-24) and the area under the bactericidal curve (AUBC), were correlated with time over MIC (T>MIC) and area under the antibiotic concentration curve divided by the MIC (AUC/MIC). RESULTS: A bactericidal effect at varying static drug concentrations was achieved for all isolates. All isolates showed similar kill curve profiles. In the kinetic model, the effect of nitrofurantoin on E. coli displayed a 4 log reduction in cfu/mL within 6 h at 8 × MIC. The outcome parameters Δcfu0-24 and AUBC had a good correlation with T>MIC (R ≈ 0.83 and R ≈ 0.67, respectively), whereas log(AUC/MIC) was significantly poorer (R ≈ 0.39 and R ≈ 0.53, respectively). CONCLUSIONS: Nitrofurantoin was highly effective against E. coli and S. saprophyticus isolates; the killing effect against E. faecium was not as rapid, but still significant. Against E. coli, nitrofurantoin was mainly associated with a concentration-dependent action; this was confirmed in the kinetic model, in which T>MIC displayed the best correlation.

Evaluation of double- and triple-antibiotic combinations for VIM- and NDM-producing Klebsiella pneumoniae by in vitro time-kill experiments.

Combination therapy is recommended for infections with carbapenemase-producing Klebsiella pneumoniae. However, limited data exist on which antibiotic combinations are the most effective. The aim of this study was to find effective antibiotic combinations against metallo-beta-lactamase-producing K. pneumoniae (MBL-KP). Two VIM- and two NDM-producing K. pneumoniae strains, all susceptible to colistin, were exposed to antibiotics at clinically relevant static concentrations during 24-h time-kill experiments. Double- and triple-antibiotic combinations of aztreonam, ciprofloxacin, colistin, daptomycin, fosfomycin, meropenem, rifampin, telavancin, tigecycline, and vancomycin were used. Synergy was defined as a ≥2 log10 decrease in CFU/ml between the combination and its most active drug after 24 h, and bactericidal effect was defined as a ≥3 log10 decrease in CFU/ml after 24 h compared with the starting inoculum. Synergistic or bactericidal activity was demonstrated for aztreonam, fosfomycin, meropenem, and rifampin in double-antibiotic combinations with colistin and also for aztreonam, fosfomycin, and rifampin in triple-antibiotic combinations with meropenem and colistin. Overall, the combination of rifampin-meropenem-colistin was the most effective regimen, demonstrating synergistic and bactericidal effects against all four strains. Meropenem-colistin, meropenem-fosfomycin, and tigecycline-colistin combinations were not bactericidal against the strains used. The findings of this and other studies indicate that there is great potential of antibiotic combinations against carbapenemase-producing K. pneumoniae. However, our results deviate to some extent from those of previous studies, which might be because most studies to date have included KPC-producing rather than MBL-producing strains. More studies addressing MBL-KP are needed.

Little evidence for reversibility of trimethoprim resistance after a drastic reduction in trimethoprim use.

OBJECTIVES: The worldwide rapid increase in antibiotic-resistant bacteria has made efforts to prolong the lifespan of existing antibiotics very important. Antibiotic resistance often confers a fitness cost in the bacterium. Resistance may thus be reversible if antibiotic use is discontinued or reduced. To examine this concept, we performed a 24 month voluntary restriction on the use of trimethoprim-containing drugs in Kronoberg County, Sweden. METHODS: The intervention was performed on a 14 year baseline of monthly data on trimethoprim resistance and consumption. A three-parameter mathematical model was used to analyse the intervention effect. The prerequisites for reversion of resistance (i.e. fitness cost, associated resistance and clonal composition) were studied on subsets of consecutively collected Escherichia coli from urinary tract infections. RESULTS: The use of trimethoprim-containing drugs decreased by 85% during the intervention. A marginal but statistically significant effect on the increase in trimethoprim resistance was registered. There was no change in the clonal composition of E. coli and there was no measurable fitness cost associated with trimethoprim resistance in clinical isolates. The frequency of associated antibiotic resistances in trimethoprim-resistant isolates was high. CONCLUSIONS: A lack of detectable fitness cost of trimethoprim resistance in vitro together with a strong co-selection of other antibiotics could explain the rather disappointing effect of the intervention. The result emphasizes the low possibility of reverting antibiotic resistance once established and the urgent need for the development of new antibacterial agents.

Population pharmacokinetic analysis of colistin methanesulfonate and colistin after intravenous administration in critically ill patients with infections caused by gram-negative bacteria.

Colistin is used to treat infections caused by multidrug-resistant gram-negative bacteria (MDR-GNB). It is administered intravenously in the form of colistin methanesulfonate (CMS), which is hydrolyzed in vivo to the active drug. However, pharmacokinetic data are limited. The aim of the present study was to characterize the pharmacokinetics of CMS and colistin in a population of critically ill patients. Patients receiving colistin for the treatment of infections caused by MDR-GNB were enrolled in the study; however, patients receiving a renal replacement therapy were excluded. CMS was administered at a dose of 3 million units (240 mg) every 8 h. Venous blood was collected immediately before and at multiple occasions after the first and the fourth infusions. Plasma CMS and colistin concentrations were determined by a novel liquid chromatography-tandem mass spectrometry method after a rapid precipitation step that avoids the significant degradation of CMS and colistin. Population pharmacokinetic analysis was performed with the NONMEM program. Eighteen patients (6 females; mean age, 63.6 years; mean creatinine clearance, 82.3 ml/min) were included in the study. For CMS, a two-compartment model best described the pharmacokinetics, and the half-lives of the two phases were estimated to be 0.046 h and 2.3 h, respectively. The clearance of CMS was 13.7 liters/h. For colistin, a one-compartment model was sufficient to describe the data, and the estimated half-life was 14.4 h. The predicted maximum concentrations of drug in plasma were 0.60 mg/liter and 2.3 mg/liter for the first dose and at steady state, respectively. Colistin displayed a half-life that was significantly long in relation to the dosing interval. The implications of these findings are that the plasma colistin concentrations are insufficient before steady state and raise the question of whether the administration of a loading dose would benefit critically ill patients.

Sustained reduction of antibiotic use and low bacterial resistance: 10-year follow-up of the Swedish Strama programme.

Increasing use of antibiotics and the spread of resistant pneumococcal clones in the early 1990s alarmed the medical profession and medical authorities in Sweden. Strama (Swedish Strategic Programme for the Rational Use of Antimicrobial Agents and Surveillance of Resistance) was therefore started in 1994 to provide surveillance of antibiotic use and resistance, and to implement the rational use of antibiotics and development of new knowledge. Between 1995 and 2004, antibiotic use for outpatients decreased from 15.7 to 12.6 defined daily doses per 1000 inhabitants per day and from 536 to 410 prescriptions per 1000 inhabitants per year. The reduction was most prominent in children aged 5-14 years (52%) and for macrolides (65%). During this period, the number of hospital admissions for acute mastoiditis, rhinosinusitis, and quinsy (peritonsillar abscess) was stable or declining. Although the epidemic spread in southern Sweden of penicillin-resistant Streptococcus pneumoniae was curbed, the national frequency increased from 4% to 6%. Resistance remained low in most other bacterial species during this period. This multidisciplinary, coordinated programme has contributed to the reduction of antibiotic use without measurable negative consequences. However, antibiotic resistance in several bacterial species is slowly increasing, which has led to calls for continued sustained efforts to preserve the effectiveness of available antibiotics.

Strama--a Swedish working model for containment of antibiotic resistance.

The overall aim of Strama (The Swedish Strategic Programme Against Antibiotic Resistance) is to preserve the effectiveness of antibiotics in humans and animals. Strama is organised at two levels: a network of independent local multidis ciplinary groups in each county that provide prescribers with feedback on antibiotic use and resistance and implement guidelines; and a national executive working group funded by the government. To gain an insight into antibiotic use, Strama has conducted several large diagnosis prescribing surveys in primary care, in the hospital settings and in nursing homes. National antibiotic susceptibility data for Sweden and mandatory notification show that in recent years the proportion of Streptococcus pneumoniae with decreased sensitivity to penicillin V has stabilised (around 6 %), but the number of notified cases of meticillin-resistant Staphylococcus aureus (MRSA)has increased and ESBL-producing Enterobacteraceae have turned into an endemic situation. Still, Sweden is among the countries with the lowest rates of MRSA (<1 %), S. pneumoniae can still be treated with penicillin V and the rate of Escherichia coli-producingESBLs is below 5 %. Strama's activities have contributed to a steady decrease in antibiotic use from the mid 1990s until 2004(when total use slowly started to increase again) without measurable negative consequences. Regular collaboration with national and regional news media has been one of the key strategies.

A new in-vitro kinetic model to study the pharmacodynamics of antifungal agents: inhibition of the fungicidal activity of amphotericin B against Candida albicans by voriconazole.

The aim of this study was to develop and validate a new in-vitro kinetic model for the combination of two drugs with different half-lives, and to use this model for the study of the pharmacodynamic effects of amphotericin B and voriconazole, alone or in combination, against a strain of Candida albicans. Bolus doses of voriconazole and amphotericin B were administered to a starting inoculum of C. albicans. Antifungal-containing medium was eliminated and replaced by fresh medium using a peristaltic pump, with the flow-rate adjusted to obtain the desired half-life of the drug with the shorter half-life. A computer-controlled dosing pump compensated for the agent with the longer half-life. Voriconazole and amphotericin B half-lives were set to 6 and 24 h, respectively. Pharmacokinetic parameters were close to target values when both single doses and sequential doses were simulated. Voriconazole and amphotericin B administered alone demonstrated fungistatic and fungicidal activity, respectively. Simultaneous administration resulted in fungicidal activity, whereas pre-exposure of C. albicans to voriconazole, followed by amphotericin at 8 and 32 h, resulted in fungistatic activity similar to that observed with voriconazole alone. Using this model, which allowed a combination of antifungal agents with different half-lives, it was possible to demonstrate an antagonistic effect of voriconazole on the fungicidal activity of amphotericin B. The characteristics and clinical relevance of this interaction require further investigation.

Short summary of Swedres 2005, a report on Swedish antibiotic utilisation and resistance.

"Swedres 2005", the fifth report on Swedish antibiotic utilisation and resistance in human medicine, was presented in May 2006. Compared with the rest of Europe, antibiotic consumption and resistance levels in Sweden are relatively low. However, global travel and trade facilitate the spread of bacteria between countries and continents. As a consequence, also in Sweden, increasing resistance trends are seen for some pathogens, notably ESBL-producing enterobacteriaceae.

Colonisation and infection with resistant gram-positive cocci. Epidemiology and risk factors.

Only a few years after the introduction of penicillin, resistant staphylococci were isolated in hospitals. This situation has led to the development of semisynthetic penicillins. Today, multiresistant Gram-positive bacteria have become an increasing problem in both hospitals and the community, frequently leaving the glycopeptides as the only therapeutic option. Notable problem pathogens are methicillin-resistant Staphylococcus aureus, coagulase-negative staphylococci and glycopeptide-resistant enterococci in the nosocomial environment, and penicillin-resistant Streptococcus pneumoniae in the community. In the hospital setting, as well as in the community and in animal husbandry, crowding and poor hygiene can facilitate the spread of resistant bacteria selected by antibiotic usage. However, the precise epidemiology and frequency of each drug-resistant pathogen depends on geographical location, the patient group involved and previous antibiotic use. Active measures need to be taken to reduce the spread of these pathogens and thus preserve the efficacy of available antibiotics.

Oral empiric treatment of community-acquired pneumonia. A multicenter, double-blind, randomized study comparing sparfloxacin with roxithromycin. The Scandinavian Sparfloxacin Study Group.

STUDY OBJECTIVE: Comparison of efficacy and safety of sparfloxacin (Spfx) vs roxithromycin (ROXI) for treatment of community-acquired pneumonia (CAP). DESIGN: Multicenter, double-blind, randomized study. SETTING: Twenty-three university and community hospitals in Scandinavia. PATIENTS: Three hundred four adults (> or = 18 years of age) with CAP treated as outpatients (25%) or inpatients (75%). INTERVENTIONS: Randomization 1:1 to Spfx, 400 mg on day 1, then 200 mg once daily, or ROXI, 150 mg twice daily, 10 to 14 days. Safety and efficacy analyses in intention-to-treat (ITT) and evaluable populations. RESULTS: Three hundred three of 304 patients were included in the ITT and safety analyses and 260 (86%) were evaluable at the end of follow-up. Streptococcus pneumoniae was the cause of pneumonia in 62 (20%) patients (11 with bacteremia), Chlamydia pneumoniae in 40 (13%), and Mycoplasma pneumoniae in 38 (13%) patients. The success rates for Spfx and ROXI at the end of follow-up were 82% and 72%, respectively, in the ITT population, and 94% and 79%, respectively, in the evaluable population. The odds ratio Spfx/ROXI for success was 4.5 (95% confidence interval, 1.9, 10.8) for the evaluable population. Both drugs were, overall, equally safe. GI symptoms were the most common adverse experiences in both groups. Prolongation of QTc, without clinical symptoms, was seen in 3% of Spfx patients and in 1% of ROXI patients, and photosensitivity, mostly mild to moderate, was seen in 5% of the Spfx group. CONCLUSIONS: Oral treatment with Spfx was superior to ROXI for the treatment of moderately severe CAP. Spfx was effective for all isolated pathogens, including S pneumoniae, and may be an alternative for empiric treatment of CAP, especially in areas with a high incidence of beta-lactam-resistant pneumococci.

Efficacy of beta-lactam antibiotics: integration of pharmacokinetics and pharmacodynamics.

The study of pharmacokinetics teaches us how drugs are distributed and eliminated, whereas, pharmacodynamics looks at the relationship between drug concentration and drug activity. The free, nonprotein-bound fraction of the serum concentration can be used as a surrogate marker for the levels at the site of infection. It is tempting to use tissue levels for this purpose, but their use is fraught with difficulties. The single pharmacodynamic parameter that correlates best with therapeutic efficacy for beta-lactam antibiotics is time that free serum levels stay above the minimum inhibitory concentration (MIC). Recent clinical studies seem to confirm the value of time above MIC in predicting clinical and bacteriological outcome.

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.

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.

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.

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.

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.

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.

Pharmacokinetics of intravenous cefuroxime during intermittent and continuous arteriovenous hemofiltration.

The pharmacokinetics of cefuroxime were determined in ten patients during intermittent hemofiltration (IHF) and in three patients during continuous arteriovenous hemofiltration (CAVH). All patients received a bolus dose of 1.5 g of cefuroxime intravenously and the concentrations of cefuroxime in serum and ultrafiltrate were followed during the hemofiltration period and up to 16 hours after injection of cefuroxime. During IHF the mean terminal half-life of cefuroxime was 1.6 +/- 0.3 hours compared with a terminal half-life of 21.7 +/- 5 hours after treatment. The total cefuroxime clearance was 120 +/- 22 ml/min. The hemofiltration clearance represented 86% of the total clearance and the hemofiltration process removed in average 63% of the dose. During CAVH the terminal half-life of cefuroxime was 7.9 +/- 2.2 hours. The total plasma clearance for cefuroxime was 32 +/- 7.5 ml/min where the CAVH-treatment represented only 34% of the total clearance. From these data we suggest that a full loading dose (1.5 g of cefuroxime) should be given after each intermittent hemofiltration treatment when performed every second day. In CAVH, where nonrenal clearance will influence the dosage scheme significantly, we suggest an initial dose of 1.5 g of cefuroxime to be followed by a supplementary dose of 750 mg every 20-24 h.

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.

A micromethod for determination of antimicrobial agents in bone.

A microtechnique, requiring very small amounts of tissue material, was developed for assay of antimicrobial agents in bone. Without previous homogenization or extraction, small bone pieces (mean weight 0.014 g) from human subjects and pigs were placed into wells in agar plates preinoculated with the test strain. Round and distinct zones of inhibition were formed around the pieces. Standards for ampicillin and flucloxacillin were prepared from freeze-dried bone pieces from human subjects and pigs with known amounts of antibiotics as well as in human plasma and phosphate-buffered saline (PBS). Curves obtained from these standards were linear. Bone pieces from human and pig maxilla gave superimposable curves, but differed from curves obtained in plasma or PBS. The method was used in a pharmacokinetic study of bacampicillin in human maxillary bone and plasma. Bacampicillin tablets (2 X 400 mg) were given to patients before oral surgery. Standardized bone pieces and plasma samples were obtained at different times during surgery. The peak ampicillin concentrations estimated from the population curves were 8.0 mg/l in plasma and 1.1 mg/l in maxillary bone. The elimination half-life of ampicillin was similar in plasma and maxillary bone.