No abstract

The causes of antibiotic resistance are complex and include human behaviour at many levels of society; the consequences aff ect everybody in the world. Similarities with climate change are evident. Many eff orts have been made to describe the many diff erent 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 eff ective 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.

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.

5During the last decade, the efforts to combat multidrugresistant (MDR) microorganisms mainly focused on gram-positive bacteria, namely, methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci. While a large number of hospitals have implemented more rigorous infection control measures, drug companies have developed novel antimicrobial agents to combat these bacteria, resulting in several new compounds with novel mechanisms of action, e.g., linezolid and daptomycin (66). Paralleling the developments in gram-positive bacteria, infections caused by MDR gram-negative bacilli have become a growing problem (71). In a recent report the Infectious Diseases Society of America specifically addressed three categories of MDR gram-negative bacilli, namely, extended-spectrum cephalosporin-resistant Escherichia coli and Klebsiella spp., MDR Pseudomonas aeruginosa, and carbapenem-resistant Acinetobacter spp. (70). Unfortunately, and contrary to what happened with gram-positive bacteria, no antibiotic from a new class has been developed specifically for MDR gram-negative bacilli. It might be argued that the glycylcycline tigecycline is an exception from the statement made above, but although this drug has in vitro activity against many MDR gram-negative bacilli, the drug was not developed specifically for the purpose of treating infections caused by such bacteria (64). Moreover, there are now a growing number of reports of cases of infections caused by gram-negative organisms for which no adequate therapeutic options exist (20). This return to the preantibiotic era has become a reality in many parts of the world (14, 55, 80). The present report aims at estimating the prevalence of infections due to MDR gramnegative bacilli, as well as the consequences with respect to mortality, hospital length of stay (LOS), and increased hospital costs.The topics covered in this report are resistance to extendedspectrum cephalosporins in E. coli and Klebsiella pneumoniae, MDR (resistance to three or more antipseudomonal agents) (17) in P. aeruginosa, and carbapenem resistance in Acinetobacter spp. PubMed (www.ncbi.nih.gov; accessed on 31 October 2007) searches were performed by using the following search terms: (Escherichia coli OR Klebsiella pneumoniae) AND ESBL, (Escherichia coli OR Klebsiella pneumoniae) AND cephalosporin resistance, Pseudomonas AND multidrug resistance, Acinetobacter AND carbapenem resistance, antibiotic resistance AND (Pseudomonas OR Acinetobacter OR Escherichia coli OR Klebsiella) AND mortality, antibiotic resistance AND (Pseudomonas OR Acinetobacter OR Escherichia coli OR Klebsiella) AND length of stay, and antibiotic resistance AND (Pseudomonas OR Acinetobacter OR Escherichia coli OR Klebsiella) AND cost. The searches were performed to address the issues of prevalence, mortality, increased LOS, and increased hospital costs. Following the review of all abstracts, a total of 85 papers were considered relevant and were evaluated for the preparation of this report. All included papers on the clinica...

In Europe, antimicrobial resistance has been monitored since 1998 by the European Antimicrobial Resistance Surveillance System (EARSS). We examined the relationship between penicillin nonsusceptibility of invasive isolates of Streptococcus pneumoniae (an indicator organism) and antibiotic sales. Information was collected on 1998-99 resistance data for invasive isolates of S. pneumoniae to penicillin, based on surveillance data from EARSS and on outpatient sales during 1997 for beta-lactam antibiotics and macrolides. Our results show that in Europe antimicrobial resistance is correlated with use of beta-lactam antibiotics and macrolides.