[Low dosage CT better than conventional radiography in the diagnosis of rhinosinusitis--a comment from the Medical Products Agency and Strama]
Using a liquid chromatography-tandem mass spectrometry method, the serum and cerebrospinal fluid (CSF) concentrations of colistin were determined in patients aged 11/2 months to 14 years receiving intravenous colistimethate sodium (60,000 to 225,000 IU/kg of body weight/day). Only in one of five courses studied (a 14-year-old receiving 225,000 IU/kg/day) did serum concentrations exceed the 2 mu g/ml CLSI/EUCAST breakpoint defining susceptibility to colistin for Pseudomonas and Acinetobacter. CSF colistin concentrations were <0.2 mu g/ml but increased in the presence of meningitis (similar to 0.5 mu g/ml or 34 to 67% of serum levels).
Although the individual and societal consequences of antibiotic resistance spiral upwards, coordinated action has not kept pace on a global scale. The COVID-19 pandemic has highlighted the need for resilient health systems and has resulted in an unprecedented rate of collaboration in scientific, medical, social, and political dimensions. The pandemic has also created a renewed awareness of the importance of infectious diseases and is a substantial entry point for reigniting the momentum towards containing the silent pandemic of antibiotic resistance. In this Viewpoint, we discuss the limitations in the current narrative on antibiotic resistance and how it could be improved, including concerted efforts to close essential data gaps. We discuss the need for capacity building and coordination at the national and global levels to strengthen the understanding of the importance of sustainable access to effective antibiotics for all health systems that could generate tangible links to current processes for global health and development.
Antibiotic resistance has emerged as one of the greatest global health challenges to be addressed in the 21st Century. The risk of widespread antibiotic resistance threatens to mitigate the positive changes made in modernizing healthcare systems; therefore, fresh approaches are essential, as well as new and effective antibacterial drugs. In a globalized world, a spectrum of different interventions and health technologies must be employed to contain antibiotic resistance. Finding ways of accelerating the development of new drugs and diagnostic tools is one strategy, as is better surveillance of antibiotic resistance and ways of improving use of existing antibiotics. Moreover, a framework to regulate use is called for to avoid that potential new antibiotics are squandered. Finally, the ongoing pandemic spread of resistant bacteria illustrates that the problem can only be addressed through international cooperation and thus that any new strategy to manage antibiotic resistance must take into consideration issues of global access and affordability.
Universal access to effective antimicrobials is essential to the realization of the right to health. At present, 5.7 million people die from treatable infections each year because they lack this access. Yet, community-based diagnosis and appropriate treatment for many of the leading causes of avoidable infectious deaths has been shown to be feasible and effective, demonstrating that strategies to reach the under-served need to receive high priority. This is a necessary part of a broad strategy to assure the long-term benefits of antimicrobials and to combat antimicrobial resistance, both because the lack of systematic and rigorous efforts to assure effective coverage increases the likelihood of antimicrobial resistance, and because global efforts aimed at antimicrobial stewardship and innovation cannot succeed without explicitly addressing the needs of the under-served. Elements of this strategy will include clear evidence-based treatment protocols, a robust international framework and locally tailored regulations, active engagement with communities and local health providers, strong attention to program management and cost considerations, a focus on the end user, and robust surveillance and response to emerging resistance patterns. Only by balancing the needs of universal access with stewardship and innovation, and assuring that they are mutually reinforcing can a global strategy hope to effectively address antimicrobial resistance.
Two commercial databases (Pharmaprojects and Adis Insight R&D) were queried for antibacterial agents in clinical development. Particular attention was given to antibacterial agents for systemic administration. For each agent, reviewers were requested to indicate whether its spectrum of activity covered a set of selected multidrug-resistant bacteria, and whether it had a new mechanism of action or a new target. In addition, PubMed was searched for antibacterial agents in development that appeared in review articles. Out of 90 agents that were considered to fulfil the inclusion criteria for the analysis, 66 were new active substances. Fifteen of these could be systemically administered and were assessed as acting via a new or possibly new mechanism of action or on a new or possibly new target. Out of these, 12 agents were assessed as having documented in vitro activity against antibiotic-resistant Gram-positive bacteria and only four had documented in vitro activity against antibiotic-resistant Gram-negative bacteria. Of these four, two acted on new or possibly new targets and, crucially, none acted via new mechanisms of action. There is an urgent need to address the lack of effective treatments to meet the increasing public health burden caused by multidrug-resistant bacteria, in particular against Gram-negative bacteria.
BACKGROUND: We examined how prolonged antibiotic treatment affected the resistance and mutation frequency of human microflora isolated from intestine (Escherichia coli, enterococci spp.), pharynx (alpha-streptococci) and nostril (coagulase-negative staphylococci, CoNS).
METHODS: Samples were collected from patients at the Center of Cystic Fibrosis (n=18) and the haematology ward (n=18) of the University Hospital, Uppsala, Sweden. The individually used amount of antibiotics for 1 year was recorded as the defined daily dose (DDD). Primary health care patients (n=30), with no antibiotic treatment for 1 year before sampling, were used as controls. Three isolates of each bacterium from each patient were examined. Antibiotic susceptibilities were determined by disc diffusion. Mutation frequencies to rifampicin resistance were measured on 30 independent cultures of each bacterial species from each individual by plating on rifampicin agar plates. For alpha-streptococci the mutation frequency to streptomycin resistance was also determined.
RESULTS: Isolates from patients with high antibiotic use showed a pronounced shift towards increased resistance and a small but significant increase in the mutation frequency compared with isolates from the controls. For E. coli, enterococci and CoNS the increase in geometric mean mutation frequency in the patient group was 3-, 1.8- and 1.5-fold, respectively (P values 0.0001, 0.016 and 0.012). For alpha-streptococci there was a significant difference in geometric mean mutation frequency between patient and control groups for streptomycin resistance (P=0.024) but not for rifampicin resistance (P=0.74).
CONCLUSIONS: High antibiotic use selected for commensals with highly increased resistance and a slight increase in mutation frequency.
The increasing antibiotic resistance is a global threat to health care as we know it. Yet there is no model of distribution ready for a new antibiotic that balances access against excessive or inappropriate use in rural settings in low-and middle-income countries (LMICs) where the burden of communicable diseases is high and access to quality health care is low. Departing from a hypothetical scenario of rising antibiotic resistance among pneumococci, 11 stakeholders in the health systems of various LMICs were interviewed one-on-one to give their view on how a new effective antibiotic should be distributed to balance access against the risk of inappropriate use. Transcripts were subjected to qualitative 'framework' analysis. The analysis resulted in four main themes: Barriers to rational access to antibiotics; balancing access and excess; learning from other communicable diseases; and a system-wide intervention. The tension between access to antibiotics and rational use stems from shortcomings found in the health systems of LMICs. Constructing a sustainable yet accessible model of antibiotic distribution for LMICs is a task of health system-wide proportions, which is why we strongly suggest using systems thinking in future research on this issue.
The increasing prevalence of hospital and community-acquired infections caused by multidrug-resistant (MDR) bacterial pathogens is rapidly limiting the options for effective antibiotic therapy. Systematic studies on combinations of already available antibiotics that could provide an effective treatment against MDR bacteria are needed. We tested combinations of antibiotics that target one important physiological function (peptidoglycan synthesis) at several steps, and studied Enterobacteriaceae (Klebsiella pneumoniae and Escherichia coli) for which multidrug resistance associated with ESBL-producing plasmids has become a major problem. To measure the effectiveness of antibiotics alone and in combination, we used checkerboard assays, static antibiotic concentration time-kill assays, and an improved in-vitro kinetic model that simulates human pharmacokinetics of multiple simultaneously administered antibiotics. The target strains included an MDR K. pneumoniae isolate responsible for a recent major hospital outbreak. A double combination (fosfomycin and aztreonam) and a triple combination (fosfomycin, aztreonam and mecillinam) were both highly effective in reducing bacterial populations in all assays, including the in vitro kinetic model. These combinations were effective even though each of the MDR strains was resistant to aztreonam alone. Our results provide an initial validation of the potential usefulness of a combination of antibiotics targeting peptidoglycan synthesis in the treatment of MDR Gram-negative bacteria. We suggest that a combination of fosfomycin with aztreonam could become a useful treatment option for such infections and should be further studied.
The emerging problem of antibiotic resistance is a serious threat to global public health. The situation is aggravated by a substantial decline in the research and development of antibacterial agents. Hence, very few new antibacterial classes are brought to market when older classes lose their efficacy. There has been renewed and growing attention within policy groups to: (i) address the problem; (ii) discuss incentives for the development of urgently needed new treatments; (iii) preserve the efficacy of existing therapeutic options. We briefly review the basic principles of antibiotic resistance, and contrast the increasing resistance to the dwindling antibacterial 'pipeline'. We also highlight some recent policy initiatives aiming to secure the future need of effective antibiotics.
An analytical method for quantitation of colistin A and colistin B in plasma and culture medium is described. After protein precipitation with acetonitrile (ACN) containing 0.1% trifluoroacetic acid (TFA), the supernatants were diluted with 0.03% TFA. The compounds were separated on an Ultrasphere C18 column, 4.6 mm x 250 mm, 5 mu m particle size with a mobile phase consisting of 25% ACN in 0.03% TFA and detected with tandem mass spectrometry. The instrument was operating in ESI negative ion mode and the precursor-product ion pairs were m/z 1167.7 -> 1079.6 for colistin A and m/z 1153.7 -> 1065.6 for colistin B. The lower limit of quantification (LLOQ) for 100 mu L plasma was 19.4 and 10.5 ng/mL for colistin A and B, respectively, with CV <6.2% and accuracy <+/- 12.6%. For culture medium (50 mu L+ 50 mu L plasma), LLOQ was 24.2 and 13.2 ng/mL for colistin A and B, respectively, with CV <11.4% and accuracy <+/- 8.1%. The quick sample work-up method allows for determination of colistin A and B in clinical samples without causing hydrolysis of the prodrug colistin methanesulfonate (CMS).
This commentary examines how specific sustainable development goals (SDGs) are affected by antimicrobial resistance and suggests how the issue can be better integrated into international policy processes. Moving beyond the importance of effective antibiotics for the treatment of acute infections and health care generally, we discuss how antimicrobial resistance also impacts on environmental, social, and economic targets in the SDG framework. The paper stresses the need for greater international collaboration and accountability distribution, and suggests steps towards a broader engagement of countries and United Nations agencies to foster global intersectoral action on antimicrobial resistance.
Colistin adheres to a range of materials, including plastics in labware. The loss caused by adhesion influences an array of methods detrimentally, including MIC assays and in vitro time-kill experiments. The aim of this study was to characterize the extent and time course of colistin loss in different types of laboratory materials during a simulated time-kill experiment without bacteria or plasma proteins present. Three types of commonly used large test tubes, i.e., soda-lime glass, polypropylene, and polystyrene, were studied, as well as two different polystyrene microplates and low-protein-binding microtubes. The tested concentration range was 0.125 to 8 mg/liter colistin base. Exponential one-phase and two-phase functions were fitted to the data, and the adsorption of colistin to the materials was modeled with the Langmuir adsorption model. In the large test tubes, the measured start concentrations ranged between 44 and 102% of the expected values, and after 24 h, the concentrations ranged between 8 and 90%. The half-lives of colistin loss were 0.9 to 12 h. The maximum binding capacities of the three materials ranged between 0.4 and 1.1 μg/cm2, and the equilibrium constants ranged between 0.10 and 0.54 ml/μg. The low-protein-binding microtubes showed start concentrations between 63 and 99% and concentrations at 24 h of between 59 and 90%. In one of the microplates, the start concentrations were below the lower limit of quantification at worst. In conclusion, to minimize the effect of colistin loss due to adsorption, our study indicates that low-protein-binding polypropylene should be used when possible for measuring colistin concentrations in experimental settings, and the results discourage the use of polystyrene. Furthermore, when diluting colistin in protein-free media, the number of dilution steps should be minimized.
This report describes the pharmacokinetics of colistin methanesulfonate (CMS) and colistin in five intensive care unit patients receiving continuous venovenous hemodiafiltration. For CMS, the mean maximum concentration of drug in plasma (C(max)) after the fourth dose was 6.92 mg/liter and total clearance (CL) 8.23 liters/h. For colistin, the mean concentration was 0.92 mg/liter and CL/metabolized fraction (f(m)) 18.91 liters/h. Colistin concentrations were below the current MIC breakpoints, and the area under the concentration-time curve for the free, unbound fraction of the drug over 24 h in the steady state divided by the MIC (fAUC/MIC) was lower than recommended, suggesting that a dosage regimen of 160 mg CMS every 8 h (q8h) is inadequate.
Objectives: In silico pharmacokinetic/pharmacodynamic (PK/PD) models can be developed based on data from in vitro time-kill experiments and can provide valuable information to guide dosing of antibiotics. The aim was to develop a mechanism-based in silico model that can describe in vitro time-kill experiments of Escherichia coli MG1655 WT and six isogenic mutants exposed to ciprofloxacin and to identify relationships that may be used to simplify future characterizations in a similar setting. Methods: In this study, we developed a mechanism-based PK/PD model describing killing kinetics for E. coli following exposure to ciprofloxacin. WT and six well-characterized mutants, with one to four clinically relevant resistance mutations each, were exposed to a wide range of static ciprofloxacin concentrations. Results: The developed model includes susceptible growing bacteria, less susceptible (pre-existing resistant) growing bacteria, non-susceptible non-growing bacteria and non-colony-forming non-growing bacteria. The non-colony-forming state was likely due to formation of filaments and was needed to describe data close to the MIC. A common model structure with different potency for bacterial killing (EC50) for each strain successfully characterized the time-kill curves for both WT and the six E. coli mutants. Conclusions: The model-derived mutant-specific EC50 estimates were highly correlated (r(2) = 0.99) with the experimentally determined MICs, implying that the in vitro time-kill profile of a mutant strain is reasonably well predictable by the MIC alone based on the model.
Predicting competition between antibiotic-susceptible wild-type (WT) and less susceptible mutant (MT) bacteria is valuable for understanding how drug concentrations influence the emergence of resistance. Pharmacokinetic/pharmacodynamic (PK/PD) models predicting the rate and extent of takeover of resistant bacteria during different antibiotic pressures can thus be a valuable tool in improving treatment regimens. The aim of this study was to evaluate a previously developed mechanism-based PK/PD model for its ability to predict in vitro mixed-population experiments with competition between Escherichia coli (E. coli) WT and three well-defined E. coli resistant MTs when exposed to ciprofloxacin. Model predictions for each bacterial strain and ciprofloxacin concentration were made for in vitro static and dynamic time–kill experiments measuring CFU (colony forming units)/mL up to 24 h with concentrations close to or below the minimum inhibitory concentration (MIC), as well as for serial passage experiments with concentrations well below the MIC measuring ratios between the two strains with flow cytometry. The model was found to reasonably well predict the initial bacterial growth and killing of most static and dynamic time–kill competition experiments without need for parameter re-estimation. With parameter re-estimation of growth rates, an adequate fit was also obtained for the 6-day serial passage competition experiments. No bacterial interaction in growth was observed. This study demonstrates the predictive capacity of a PK/PD model and further supports the application of PK/PD modelling for prediction of bacterial kill in different settings, including resistance selection.
Objectives: The objectives of this study were to study the presence of mutators in a set of Acinetobacter baumannii isolates and to explore whether there is a correlation between mutation rates and antibiotic resistance.
Methods: The variation in mutation rate was evaluated for 237 clinical A. baumannii isolates by determining the frequency of their mutation to rifampicin resistance. For each isolate, the antibiotic resistance profile was determined by disc diffusion and/or Etest. Isolates were divided into susceptible, resistant and MDR groups according to their resistance to five groups of different antibiotics. A comparison between differences in mutation frequency (f) and strain-specific factors was performed.
Results: Of the 237 isolates 32%, 18% and 50% were classified as susceptible, resistant and MDR, respectively. The f of rifampicin resistance varied between 2.2×10210 and 1.2×1026 . Of the strains under investigation, 16% had an ≥2.5- to 166-fold higher f. The presence of mutators (definition ≥2.5-fold increase in f compared with ATCC 19606) in the MDR group (22%) was significantly higher (P,0.05) than that in the susceptible and resistant groups (11% and 7%, respectively). Furthermore, f was significantly higher in the MDR group compared with that in the susceptible and resistant groups.
Conclusions: The facts that 26 of 37 mutator isolates (70%) in the population were MDR and that there was a significantly higher general f in isolates exhibiting an MDR profile suggest that hypermutability can be of advantage for the organism in a selective environment with extensive exposure to antimicrobials.
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 andR ≈ 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.
The accuracy of using body temperature, serum amyloid A (SAA), C-reactive protein (CRP) and interleukin-6 (IL-6) in the work-up for early or late step-down therapy after an initial course of intravenous cefuroxime was investigated. Eighty-one hospitalized patients with an initial course of cefuroxime were retrospectively classified with one of the following diagnoses: bacterial infection without known focus, pneumonia, bronchitis, pyelonephritis, skin and soft-tissue infections or fever of other origin. The majority of the patients had sepsis (91% or 74/81) of whom 6 patients had severe sepsis. The inter-individual variability of body temperature, SAA, CRP and IL-6 was considerable. The time course of SAA and CRP during the first 24 h in patients with sepsis with a short duration of illness but without septic shock showed increasing levels during the initial course of intravenous therapy. In contrast, body temperature and IL-6 decreased, regardless of illness duration. Beyond 24 h, all 4 biomarkers declined, again regardless of the duration of illness. After the initial course of cefuroxime, biomarkers were non-distinguishing in terms of guidance in the judgement of early or late step-down therapy. Further studies are proposed for biomarker guidance antibiotic therapy in sepsis patients without septic shock.
The causes of antibiotic resistance are complex and include human behaviour at many levels of society; the consequences affect everybody in the world. Similarities with climate change are evident. Many efforts have been made to describe the many different facets of antibiotic resistance and the interventions needed to meet the challenge. However, coordinated action is largely absent, especially at the political level, both nationally and internationally. Antibiotics paved the way for unprecedented medical and societal developments, and are today indispensible in all health systems. Achievements in modern medicine, such as major surgery, organ transplantation, treatment of preterm babies, and cancer chemotherapy, which we today take for granted, would not be possible without access to effective treatment for bacterial infections. Within just a few years, we might be faced with dire setbacks, medically, socially, and economically, unless real and unprecedented global coordinated actions are immediately taken. Here, we describe the global situation of antibiotic resistance, its major causes and consequences, and identify key areas in which action is urgently needed.
AIM: To determine if the use of alcohol-based hand-disinfection as a complement to regular hand washing at daycare centers (DCCs) can reduce the childhood rate of absenteeism. METHODS: Children aged 0-6 years attending DCC were studied in a cluster randomized controlled trial during 30 weeks. Thirty matched pairs of DCCs were included in the study, where one of the DCCs was randomized to intervention and the other to control within each pair. The intervention consisted in children and staff using alcohol-based oily disinfectant gel containing 70% ethanol after regular hand washing. The main outcome was the rate of episodes of absence from DCC due to infection. A regression model was fitted at the individual level and controlling several possible confounders for illness. Absences were reported by the parents. RESULTS: Differences in missing absence reports between the two groups led to only evaluating those 29 DCCs (1431 children) that were able to provide complete reports. In the multivariate regression, the intervention significantly reduced the rate of absenteeism of a child by 12% compared to a child in a control DCC (IRR 95% CI: 0.799-0.965). CONCLUSION: Hand-disinfection used by children and staff significantly decreased childrens absences due to infections in Swedish DCCs.
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.
It is generally accepted that only the unbound fraction of a drug is pharmacologically active. Posaconazole is an antifungal agent with a protein binding of 98 to 99%. Taking into account the degree of protein binding, plasma levels in patients, and MIC levels of susceptible strains, it can be assumed that the free concentration of posaconazole sometimes will be too low to exert the expected antifungal effect. The aim was therefore to test the activity of posaconazole in serum in comparison with that of the calculated unbound concentrations in protein-free media. Significant differences (P < 0.05) from the serum control were found at serum concentrations of posaconazole of 1.0 and 0.10 mg/liter, with calculated free concentrations corresponding to 1× MIC and 0.1× MIC, respectively, against one Candida lusitaniae strain selected for proof of principle. In RPMI 1640, the corresponding calculated unbound concentration of 0.015 mg/liter resulted in a significant effect, whereas that of 0.0015 mg/liter did not. Also, against seven additional Candida strains tested, there was an effect of the low posaconazole concentration in serum, in contrast to the results in RPMI 1640. Fluconazole, a low-grade-protein-bound antifungal, was used for comparison at corresponding concentrations in serum and RPMI 1640. No effect was observed at the serum concentration, resulting in a calculated unbound concentration of 0.1× MIC. In summary, there was a substantially greater pharmacodynamic effect of posaconazole in human serum than could be predicted by the non-protein-bound serum concentration. A flux from serum protein-bound to fungal lanosterol 14α-demethylase-bound posaconazole is suggested.
An antagonistic effect of voriconazole on the fungicidal activity of sequential doses of amphotericin B has previously been demonstrated in Candida albicans strains susceptible to voriconazole. Because treatment failure and the need to switch to other antifungals are expected to occur more often in infections that are caused by resistant strains, it was of interest to study whether the antagonistic effect was still seen in Candida strains with reduced susceptibility to voriconazole. With the hypothesis that antagonism will not occur in voriconazole resistant strains, C. albicans strains with characterized mechanisms of resistance against voriconazole, as well as C. glabrata and C. krusei strains with differences in degree of susceptibility to voriconazole were exposed to voriconazole and amphotericin B alone, simultaneously or sequentially in an in vitro kinetic model. Amphotericin B administered alone or simultaneously with voriconazole resulted in fungicidal activity. When amphotericin B was administered after voriconazole, its activity was reduced in median 61% (range 9-94%). Voriconazole-dependent inhibition of amphotericin B activity differed significantly among the strains but was not correlated with the MIC values (correlation coefficient -0.19; P=0.65). Inhibition was found in C. albicans strains with increases in CDR1 and CDR2 expression but not in the strain with an increase in MDR1 expression. In summary, decreased susceptibility to voriconazole does not abolish voriconazole-dependent inhibition of the fungicidal activity of amphotericin B in voriconazole resistant Candida strains. The degree of interaction could not be predicted by the MIC value alone.
OBJECTIVES: The aim of the present investigation was to study and characterize the effect of voriconazole on the fungicidal activity of amphotericin B. METHODS: Four strains of Candida albicans susceptible to voriconazole were exposed to voriconazole and amphotericin B, either alone, simultaneously or sequentially in an in vitro kinetic model. Bolus doses resulting in voriconazole and amphotericin B concentrations of 0.005-5 and 2.5 mg/L, respectively, were administered. Antifungal-containing RPMI 1640 was eliminated and replaced by a fresh medium using a peristaltic pump, with a flow rate adjusted to obtain the desired half-lives. With two drugs tested, a computer-controlled dosing pump compensated for differences in the elimination rates. Using static time-kill methodology, one C. albicans strain was exposed to 5 mg/L voriconazole for varying durations followed by 2.5 mg/L amphotericin B after three repeated washes of voriconazole. RESULTS: Voriconazole and amphotericin B treatment alone resulted in fungistatic and fungicidal activities, respectively. Simultaneous administration of voriconazole and amphotericin B resulted in fungicidal activity, whereas only fungistatic activity was observed when repeated doses of amphotericin B were administered sequentially after voriconazole at 24-96 h. The inhibition of the fungicidal activity of amphotericin B was voriconazole dose-dependent, but seemed to be recovered once the voriconazole concentration fell below the MIC. The fungicidal activity was quickly regained after the removal of voriconazole, irrespective of the duration of voriconazole pre-exposure. CONCLUSIONS: Voriconazole inhibited the fungicidal effect of sequentially administered amphotericin B in a concentration- and time-dependent manner; the clinical significance of this needs further investigation.
In this paper, we argue that antibiotic resistance (ABR) raises a number of ethical problems that have not yet been sufficiently addressed. We outline four areas in which ethical issues that arise in relation to ABR are particularly pressing. First, the emergence of multidrug-resistant and extensively drug-resistant infections exacerbates traditional ethical challenges of infectious disease control, such as the restriction of individual liberty for the protection of the public's health. Second, ABR raises issues of global distributive justice, both with regard to the overuse and lack of access to antibiotics. Third, the use of antibiotics in veterinary medicine raises serious concerns for animal welfare and sustainable farming practices. Finally, the diminishing effectiveness of antibiotics leads to questions about intergenerational justice and our responsibility for the wellbeing of future generations. We suggest that current policy discussions should take ethical conflicts into account and engage openly with the challenges that we outline in this paper.
Fluoroquinolones are important antibiotics for treatment of serious infections. Increased usage has, in many countries, resulted in rapid development of resistance towards this class of antibiotics. Moreover, it has been shown that use of fluoroquinolones is associated with selection of multi-resistant bacteria, such as methicillin-resistant S. aureus and vancomycin-resistant enterococci. The risks related to overuse of fluoroquinolones among both humans and animals are reviewed and strict indications for use are suggested.
Background Appropriate antibiotic therapy is critical in the management of severe sepsis and septic shock to reduce mortality, morbidity and health costs. New methods for rapid antibiotic susceptibility testing are needed because of increasing resistance rates to standard treatment. Aims The purpose of this study was to evaluate the performance of a novel microfluidic method and the potential to directly apply this method on positive blood cultures. Methods Minimum inhibitory concentrations (MICs) of ciprofloxacin, ceftazidime, tigecycline and/or vancomycin for Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and Staphylococcus aureus were determined using a linear antibiotic concentration gradient in a microfluidic assay. Bacterial growth along the antibiotic gradient was monitored using automated time-lapse photomicrography and growth inhibition was quantified by measuring greyscale intensity changes in the images. In addition to pure culture MICs, vancomycin MICs were determined for S. aureus from spiked and clinical blood cultures following a short centrifugation step. The MICs were compared with those obtained with the Etest and for S. aureus and vancomycin also with macrodilution. Results The MICs obtained with the microfluidic assay showed good agreement internally as well as with the Etest and macrodilution assays, although some minor differences were noted between the methods. The time to possible readout was within the range of 2 to 5 h. Conclusions The examined microfluidic assay has the potential to provide rapid and accurate MICs using samples from positive clinical blood cultures and will now be tested using other bacterial species and antibiotics.
Pharmacodynamic and mutant prevention properties of the fluoroquinolone pradofloxacin (PRA) were measured against a set of 17 Escherichia coli strains carrying no, one or two known mutations conferring reduced fluoroquinolone susceptibility. The strains included susceptible wild-types, isogenic constructed mutants, isogenic selected mutants and clinical isolates. The effectiveness of PRA was determined with regard to preventing the selection of resistant mutants, using static and changing concentrations of drug. Ciprofloxacin was used as a reference drug. Minimum inhibitory concentrations (MICs) and mutant prevention concentrations (MPCs) of PRA for the susceptible wild-type strains were in the range 0.012-0.016 mg/L and 0.2-0.3 mg/L, respectively, giving a mean +/- standard deviation mutant prevention index (MPI=MPC/MIC) of 17.7 +/- 1.1. The mean MPI PRA of the 14 mutant strains was 19.2 +/- 12, and the mean MPI across all 17 strains was 18.9 +/- 10.8. In an in vitro kinetic model in which PRA was diluted with a half-life of 7h to mimic in vivo conditions, an initial concentration of PRA of 1.6-2.4 mg/L (8-10x MPC), giving a PRA AUC/MPC ratio of 73-92, and a T->MPC of 21-23 h was sufficient to prevent the selection of resistant mutants from the three susceptible wild-type strains. Dosing to reduce selection for antibiotic resistance in veterinary therapy has a role in reducing the reservoir of resistant mutants. We conclude that a level of dosing that prevents the selection of resistant mutants during therapy should be achievable in vivo.
En litteraturgenomgång kring konsekvenserna av meticillinresistens vid S aureus-bakteriemi visar att MRSA-bakteriemi är förenad med en signifikant ökad risk för dödlig utgång jämfört med MSSA-bakteriemi samt att behandling av MRSA-bakteriemi är 1,5–3 gånger dyrare än behandling av MSSA-bakteriemi.
Under 1990-talet fördubblades antalet S aureus-bakteriemier i Storbritannien, huvudsakligen på grund av spridning av två epidemiska MRSA-stammar på brittiska sjukhus. En utveckling i Sverige till en situation liknande den i Storbritannien skulle grovt räknat innebära ett tillskott av 637 dödsfall årligen och kraftigt ökade kostnader.
Eftersom utvecklingen av antibiotika med nya verkningsmekanismer står stilla är det högaktuellt att vi vidtar åtgärder mot fortsatt spridning av antibiotikaresistens i Sverige.
OBJECTIVES: An optimized dosing regimen of the prodrug of colistin, colistin methanesulphonate (CMS), against resistant Pseudomonas aeruginosa is needed to ensure effective bacterial killing. The objectives of this study were to develop a pharmacokinetic (PK)/pharmacodynamic (PD) model that characterizes the time course of the antibacterial activity of colistin against P. aeruginosa in a static in vitro system and to perform simulations of different dosing regimens and dosing algorithms to evaluate the effect of interindividual variability and interoccasion variability in PK on bacterial killing.
METHODS: Static in vitro time-kill curve experiments were conducted on two different strains of P. aeruginosa (MIC 1 and 1.5 mg/L). Mechanism-based PK/PD models were fitted in NONMEM7 and the final model was combined with a previously developed population PK model of CMS and colistin to perform simulations of variability based on different dosing algorithms.
RESULTS: A model with compartments for growing and resting bacteria, with a function allowing the maximal bacterial killing of colistin to reduce upon increasing colistin exposure, characterized both the fast bactericidal effect and the adaptive resistance. The variability in PK was shown to translate into pronounced interoccasion variability in bacterial killing. A flat fixed loading dose was demonstrated to result in less variability than an algorithm based on weight.
CONCLUSIONS: The developed PK/PD model described the growth, death and resistance development of P. aeruginosa in response to colistin for two different strains. Based on simulations, a flat fixed loading dose followed by an 8 or 12 hourly maintenance dose with an infusion duration of up to 2 h appeared adequate.
OBJECTIVES: Combination therapy can be a strategy to ensure effective bacterial killing when treating Pseudomonas aeruginosa, a Gram-negative bacterium with high potential for developing resistance. The aim of this study was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model that describes the in vitro bacterial time-kill curves of colistin and meropenem alone and in combination for one WT and one meropenem-resistant strain of P. aeruginosa.
METHODS: In vitro time-kill curve experiments were conducted with a P. aeruginosa WT (ATCC 27853) (MICs: meropenem 1 mg/L; colistin 1 mg/L) and a meropenem-resistant type (ARU552) (MICs: meropenem 16 mg/L; colistin 1.5 mg/L). PK/PD models characterizing resistance were fitted to the observed bacterial counts in NONMEM. The final model was applied to predict the bacterial killing of ARU552 for different combination dosages of colistin and meropenem.
RESULTS: A model with compartments for growing and resting bacteria, where the bacterial killing by colistin reduced with continued exposure and a small fraction (0.15%) of the start inoculum was resistant to meropenem, characterized the bactericidal effect and resistance development of the two antibiotics. For a typical patient, a loading dose of colistin combined with a high dose of meropenem (2000 mg q8h) was predicted to result in a pronounced kill of the meropenem-resistant strain over 24 h.
CONCLUSIONS: The developed PK/PD model successfully described the time course of bacterial counts following exposures to colistin and meropenem, alone and in combination, for both strains, and identified a dynamic drug interaction. The study illustrates the application of a PK/PD model and supports high-dose combination therapy of colistin and meropenem to overcome meropenem resistance.
Gentamicin is commonly used in the management of neonatal infections. Development of adaptive resistance is typical for aminoglycosides and reduces the antibacterial effect. There is, however, a lack of understanding of how this phenomenon influences the effect of different dosing schedules. The aim was to develop a pharmacokinetic-pharmacodynamic (PKPD) model that describes the time course of the bactericidal activity of gentamicin and its adaptive resistance and to investigate different dosing schedules in preterm and term newborn infants based on the developed model. In vitro time-kill curve experiments were conducted on a strain of Escherichia coli (MIC of 2 mg/liter). The gentamicin exposure was either constant (0.125 to 16 mg/liter) or dynamic (simulated concentration-time profiles in a kinetic system with peak concentrations of 2.0, 3.9, 7.8, and 16 mg/liter given as single doses or as repeated doses every 6, 12, or 24 h). Semimechanistic PKPD models were fitted to the bacterial counts in the NONMEM (nonlinear mixed effects modeling) program. A model with compartments for growing and resting bacteria, with a function allowing the maximal bacterial killing of gentamicin to reduce with exposure, characterized both the fast bactericidal effect and the adaptive resistance. Despite a lower peak concentration, preterm neonates were predicted to have a higher bacterial killing effect than term neonates for the same per-kg dose because of gentamicin's longer half-life. The model supported an extended dosing interval of gentamicin in preterm neonates, and for all neonates, dosing intervals of 36 to 48 h were as effective as a 24-h dosing interval for the same total dose.
A previous pharmacokinetic study on dosing of colistin methanesulfonate (CMS) at 240 mg (3 million units [MU]) every 8 h indicated that colistin has a long half-life, resulting in insufficient concentrations for the first 12 to 48 h after initiation of treatment. A loading dose would therefore be beneficial. The aim of this study was to evaluate CMS and colistin pharmacokinetics following a 480-mg (6-MU) loading dose in critically ill patients and to explore the bacterial kill following the use of different dosing regimens obtained by predictions from a pharmacokinetic-pharmacodynamic model developed from an in vitro study on Pseudomonas aeruginosa. The unbound fractions of colistin A and colistin B were determined using equilibrium dialysis and considered in the predictions. Ten critically ill patients (6 males; mean age, 54 years; mean creatinine clearance, 82 ml/min) with infections caused by multidrug-resistant Gram-negative bacteria were enrolled in the study. The pharmacokinetic data collected after the first and eighth doses were analyzed simultaneously with the data from the previous study (total, 28 patients) in the NONMEM program. For CMS, a two-compartment model best described the pharmacokinetics, and the half-lives of the two phases were estimated to be 0.026 and 2.2 h, respectively. For colistin, a one-compartment model was sufficient and the estimated half-life was 18.5 h. The unbound fractions of colistin in the patients were 26 to 41% at clinical concentrations. Colistin A, but not colistin B, had a concentration-dependent binding. The predictions suggested that the time to 3-log-unit bacterial kill for a 480-mg loading dose was reduced to half of that for the dose of 240 mg.
Over the last decades, numerous papers have appeared--and still are appearing--that describe concentrations in tissues in an effort to predict the efficacy of an antimicrobial agent based on these concentrations and MICs for microorganisms. A common method is to use measurements of concentrations in tissue homogenates, comparing these with values derived from the corresponding blood samples and on that basis draw conclusions with respect to the potential clinical use of the drug. This approach is not justifiable for a number of reasons that includes both pharmacokinetic as well as pharmacodynamic causes. This way of presenting data with the derived conclusions is often misleading and may ultimately be harmful in patient care.