Otto Cars

• MD PhD
• Professor at Uppsala University

Co-administering a low dose of colistin (CST) with ciprofloxacin (CIP) may improve the antibacterial effect against resistant Escherichia coli, offering an acceptable benefit-risk balance. This study aimed to quantify the interaction between ciprofloxacin and colistin in an in silico pharmacokinetic-pharmacodynamic model from in vitro static time-k...

Sustainable access to effective antibiotics is a foundational need for functioning health care that is increasingly threatened by antibiotic resistance. Although resistance has been known as long as antibiotics have been in clinical use, there are still multiple gaps in the global and local responses. One often cited cause for this complacency is t...

Securing equitable antibiotic access as an essential component for health system resilience and pandemic preparedness requires a systems perspective. This article discusses key components that need to be coordinated and paired with adequate financing and resources to ensure antibiotic effectiveness as a global public good, which should be central w...

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 pandem...

Background: The spread of antibiotic-resistant bacteria poses a substantial threat to morbidity and mortality worldwide. Due to its large public health and societal implications, multidrug-resistant tuberculosis has been long regarded by WHO as a global priority for investment in new drugs. In 2016, WHO was requested by member states to create a p...

Increasing use of antibiotics and rising levels of bacterial resistance to antibiotics are a challenge to global health and development. Successful initiatives for containing the problem need to be communicated and disseminated. In Sweden, a rapid spread of resistant pneumococci in the southern part of the country triggered the formation of the Swe...

Predicting competition between antibiotic susceptible wild-type and less susceptible mutant bacteria is valuable for understanding how drug concentrations influence emergence of resistance. Pharmacokinetic-pharmacodynamic (PKPD) models predicting the rate and extent of takeover of resistant bacteria during different antibiotic pressures can thereby...

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 simulate...

Background: In view of the paucity of clinical evidence, in vitro studies are needed to find antibiotic combinations effective against multidrug-resistant Gram-negative bacteria. Interpretation of in vitro effects is usually based on bacterial growth after 24 h in time-kill and checkerboard experiments. However, the clinical relevance of the effect...

MIC values of quality control strains at different time points. MIC values (mg/L) as determined from the CellDirector 3D assay at 5, 4, 3, 2 and 1 h and percent agreement compared with the MIC determined at 5 h for P. aeruginosa with ceftazidime, E. coli with ciprofloxacin, ceftazidime and tigecycline and K. pneumoniae with ciprofloxacin. (PDF)

Time to readout in CellDirector 3D for clinical blood cultures. Thirteen isolates of S. aureus were extracted from blood bottles after positive signal for growth in BacT/Alert® 3D and identification using microscopy and coagulase test. The samples were analysed in the CellDirector 3D system by collecting an image every 10 minutes. The calculated MI...

MIC values for different inocula of VSSA and P. aeruginosa at different time points. MIC values (mg/L) as determined from the CellDirector 3D assay at 5, 4, 3, 2 and 1 h and percent agreement compared with the MIC determined at 5 h for (a) S. aureus with vancomycin and (b) P. aeruginosa with ciprofloxacin at different inocula. (PDF)

MIC values for VSSA and hVISA at different time points. MIC values (mg/L) as determined from the CellDirector 3D assay at 5, 4, 3, 2 and 1h and percent agreement compared to the MIC determined at 5h for S. aureus VSSA and hVISA (from pure cultures and spiked blood cultures) with vancomycin. (PDF)

MIC values from CellDirector 3D, Etest and macrodilution for VSSA and hVISA. MIC values for VSSA and hVISA strains determined by CellDirector 3D, Etest and Macrodilution from pure cultures and from spiked blood culture bottles. (PDF)

Recovery of bacteria from clinical blood bottles. Percent recovery and bacterial concentrations before and after centrifugation of clinical blood bottles. (PDF)

Diffusion of vancomycin in CellDirector3D. (PDF)

MIC values from CellDirector 3D and Etest for quality control strains. MIC values for QC strains determined by Etest and CellDirector 3D from pure cultures at the optimal inoculum size. (PDF)

Population analysis of VSSA and hVISA with vancomycin. Population analysis of VSSA and hVISA strains using vancomycin agar plates with 0, 0.25, 0.5, 1, 2, 3, 4 and 5 mg/L antibiotic concentration and overnight incubation. The number of surviving colonies represent fraction of resistant sub-populations at the tested concentration. Error bars denote...

Recovery of bacteria from spiked blood bottles. Percent recovery and bacterial concentrations before and after centrifugation of spiked blood bottles. (PDF)

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 performanc...

The objective of this study was to update a 2011 survey, conducted on behalf of the ESCMID Study Group for Antibiotic Policies (ESGAP), studying the availability of old but clinically useful antibiotics in North America, Europe and Australia. This follow-up survey was performed in 2015 in 40 countries among specialists from the pharmaceutical, infe...

Antibiotic resistance is a complex global health challenge. The recent Global Action Plan on antimicrobial resistance highlights the importance of adopting One Health approaches that can cross traditional disciplinary boundaries. We report on the early experiences of a multisectoral Sino-Swedish research project that aims to address gaps in our cur...

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 antimicrobi...

Ryan and colleagues' 4 initial analysis suggests that the Quality and Outcomes Framework was associated with small reductions in a composite measure of mortality and mortality for ischaemic heart disease, and with small increases in mortality for non-targeted conditions—consistent with previous research showing improvements in process measures and...

This study sought to analyse antimicrobial pressure, indications for treatment, and compliance with treatment recommendations and to identify possible problem areas where inappropriate use could be improved through interventions by the network of the local Swedish Strategic Programme Against Antibiotic Resistance (Strama) groups. Five point-prevale...

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...

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 tradition...

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 feasibl...

On March 11, 2015, we all have lost a mentor, colleague, and friend, Professor William Alexander Craig.…. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Changes in patterns of antibiotic use in Chinese hospitals before and after intensive nationwide interventions are reported and compared with Chinese national targets and antibiotic use in Swedish hospitals. Chinese data were collected quarterly and yearly from selected patient prescriptions/medical records and medicines inventory control systems f...

In the face of diminishing therapeutic options for the treatment of infections caused by multidrug-resistant, Gram-negative bacteria, dinicians are increasingly using colistin and polymyxin B. These antibiotics became available clinically in the 1950s, when understanding of antimicrobial pharmacology and regulatory requirements for approval of drug...

The global burden of antibiotic resistance is tremendous and, without new anti-infective strategies, will continue to increase in the coming decades. Despite the growing need for new antibiotics, few pharmaceutical companies today retain active antibacterial drug discovery programmes. One reason is that it is scientifically challenging to discover...

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 Enterococc...

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 cli...

Two major ways that modern medicine saves lives are through antibiotic treatment of severe infections and the performance of medical and surgical procedures under the protection of antibiotics. Yet we have not kept pace with the ability of many pathogens to develop resistance to antibiotics that are legacies of the golden era of antibiotic discover...

Objectives Today, few new antibiotics are being developed, especially against Gram-negatives. Novel uses for established drugs, especially new combination regimens, need to be studied to address the rapidly increasing problem of multi-drug resistant bacteria. Understanding the mechanisms of combination effects could guide the search for drug combin...

Objectives Acinetobacter baumannii is a troublesome opportunistic pathogen due to its multidrug resistance (MDR) and adaptability to the hospital environment. In a world lacking effective antibiotics and few novel drugs under development, older drugs like colistin (COL) is commonly used for treatment. However, resistance to COL is already appearin...

Abstract 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 qual...

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...

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 colisti...

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 (Cmax) after the fourth dose was 6.92 mg/liter and total clearance (CL) 8.23 liters/h. For colistin, the mean con...

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, c...

Polymyxins (polymyxin B and colistin) are older bactericidal antibiotics that are increasingly used to treat infections caused by multidrug-resistant (MDR) Gram-negative bacteria. However, dosing and clinical use of these drugs vary widely. This survey was undertaken to reveal how polymyxins are used worldwide. Data were collected through a structu...

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 com...

Objectives: Ertapenem resistance is increasing in Enterobacteriaceae. The production of extended-spectrum β-lactamases (ESBLs) and reduced expression of outer membrane porins are major mechanisms of resistance in ertapenem-resistant Klebsiella pneumoniae. Less is known of ertapenem resistance in Escherichia coli. The aim of this study was to explo...

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...

A-030 - Colistin, Tigecycline and Daptomycin combinations improves bacterial kill of Acinetobacter baumannii Background In a world lacking effective antibiotics for treatment of MDR bacteria and few drugs under development there is an urgent need for new data on how and what drugs to use in therapy. New facts will help to expand the lifespan of e...

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 CM...

The stream of new antibiotics is struggling to keep up with emerging bacterial resistance. Anthony So and colleagues examine what can be done to increase innovation The dearth of novel antibiotics poses challenges to the treatment of bacterial infection and points to shortcomings in the system of pharmaceutical innovation. Increasing bacterial res...

Multidrug-resistant Gram-negative organisms - old and new strategies Monday, April 02, 2012, 12:30 - 13:30 Colistin in combination with daptomycin enhances the effect against A. baumannii C. Malmberg*, L. Albrecht, P. Bertilsson-Forsberg, P. Lagerbäck, H. Seifert, P. Komp-Lindgren, O. Cars (Uppsala, SE; Cologne, DE) Objectives: Multi-drug resistant...

A pharmacokinetic-pharmacodynamic (PKPD) model that characterizes the full time course of in vitro time-kill curve experiments of antibacterial drugs was here evaluated in its capacity to predict the previously determined PK/PD indices. Six drugs (benzylpenicillin, cefuroxime, erythromycin, gentamicin, moxifloxacin, and vancomycin), representing a...

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 som...

Although the influence of protein binding (PB) on antibacterial activity has been reported for many antibiotics and over many years, there is currently no standardization for pharmacodynamic models that account for the impact of protein binding of antimicrobial agents in vitro. This might explain the somewhat contradictory results obtained from dif...

We have previously described a general semimechanistic pharmacokinetic-pharmacodynamic (PKPD) model that successfully characterized the time course of antibacterial effects seen in bacterial cultures when exposed to static concentrations of five antibacterial agents of different classes. In this PKPD model, the total bacterial population was divide...

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, i...

During an outbreak of extended-spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae at our hospital, we performed an educational antibiotic intervention aimed at reducing prescriptions of second- and third-generation cephalosporins and preventing increased use of fluoroquinolones and carbapenems. In this report, we describe the implementatio...

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...

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...

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 Enteroc...

Aim The aim of the study was to evaluate the impact of hygiene routines and characteristics of the daycare centre (DCC) on sickness absence in preschool children. Background In Sweden most children attend daycare outside home during daytime. Daycare outside home results in cognitive and social gains for the children, but it also increases the risk...

Foreign travel has been suggested to be a risk factor for the acquisition of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae. To our knowledge, this has not previously been demonstrated in a prospective study. Healthy volunteers traveling outside Northern Europe were enrolled. Rectal swabs and data on potential travel-associate...

Using a liquid chromatography-tandem mass spectrometry method, the serum and cerebrospinal fluid (CSF) concentrations of colistin were determined in patients aged 1 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/d...

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...

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...

216 patients aged >7 years with febrile group A streptococcal pharyngotonsillitis were randomly assigned to 3 treatment groups receiving either phenoxymethylpenicillin for 5 days followed by placebo for 5 days, phenoxymethylpenicillin for 10 days, or cefadroxil for 10 days. 209 patients completed treatment, 70 subjects in each phenoxymethylpenicill...

Mutation frequency of rifampicin resistance in Acinetobacter baumannii clinical isolates Abstract number: O443 Komp Lindgren P., Seifert H., Cars O. Objectives: To study the differences in mutation frequency and evaluate the possible correlations between drug resistance development and mutation rate in Acinetobacter baumannii (AB). Methods: The...

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...

An approach for estimation of dosing strategies based on data-derived models and assessment of the risk associated with deviation from the treatment target is presented. The work is illustrated by establishing a dosing strategy to be used for a priori individualization on the basis of renal function for the antibiotic cefuroxime. Treatment involved...