Development of ceftazidime resistance in an acute Burkholderia pseudomallei infection

Derek S Sarovich,1,2,* Erin P Price,1,2,* Direk Limmathurotsakul,3 James M Cook,1 Alex T Von Schulze,1 Spenser R Wolken,1 Paul Keim,1 Sharon J Peacock,3,4 Talima Pearson1 1Center for Microbial Genetics and Genomics, Northern Arizona University, Flagstaff, AZ, USA; 2Tropical and Emerging Infectious Diseases Division, Menzies School of Health Research, Darwin, Australia; 3Department of Microbiology and Immunology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; 4Department of Medicine, University of Cambridge, Cambridge, United Kingdom*These authors contributed equally to this workAbstract: Burkholderia pseudomallei, a bacterium that causes the disease melioidosis, is intrinsically resistant to many antibiotics. First-line antibiotic therapy for treating melioidosis is usually the synthetic β-lactam, ceftazidime (CAZ), as almost all B. pseudomallei strains are susceptible to this drug. However, acquired CAZ resistance can develop in vivo during treatment with CAZ, which can lead to mortality if therapy is not switched to a different drug in a timely manner. Serial B. pseudomallei isolates obtained from an acute Thai melioidosis patient infected by a CAZ susceptible strain, who ultimately succumbed to infection despite being on CAZ therapy for the duration of their infection, were analyzed. Isolates that developed CAZ resistance due to a proline to serine change at position 167 in the β-lactamase PenA were identified. Importantly, these CAZ resistant isolates remained sensitive to the alternative melioidosis treatments; namely, amoxicillin-clavulanate, imipenem, and meropenem. Lastly, real-time polymerase chain reaction-based assays capable of rapidly identifying CAZ resistance in B. pseudomallei isolates at the position 167 mutation site were developed. The ability to rapidly identify the emergence of CAZ resistant B. pseudomallei populations in melioidosis patients will allow timely alterations in treatment strategies, thereby improving patient outcomes for this serious disease.Keywords: Burkholderia pseudomallei, ceftazidime, antibiotic resistance, melioidosis, β-lactamase, pen

Development of ceftazidime resistance in an acute Burkholderia pseudomallei infection.

Burkholderia pseudomallei, a bacterium that causes the disease melioidosis, is intrinsically resistant to many antibiotics. First-line antibiotic therapy for treating melioidosis is usually the synthetic β-lactam, ceftazidime (CAZ), as almost all B. pseudomallei strains are susceptible to this drug. However, acquired CAZ resistance can develop in vivo during treatment with CAZ, which can lead to mortality if therapy is not switched to a different drug in a timely manner. Serial B. pseudomallei isolates obtained from an acute Thai melioidosis patient infected by a CAZ susceptible strain, who ultimately succumbed to infection despite being on CAZ therapy for the duration of their infection, were analyzed. Isolates that developed CAZ resistance due to a proline to serine change at position 167 in the β-lactamase PenA were identified. Importantly, these CAZ resistant isolates remained sensitive to the alternative melioidosis treatments; namely, amoxicillin-clavulanate, imipenem, and meropenem. Lastly, real-time polymerase chain reaction-based assays capable of rapidly identifying CAZ resistance in B. pseudomallei isolates at the position 167 mutation site were developed. The ability to rapidly identify the emergence of CAZ resistant B. pseudomallei populations in melioidosis patients will allow timely alterations in treatment strategies, thereby improving patient outcomes for this serious disease

Photoionization Spectroscopy of Nucleobasesand Analogues in the Gas Phase UsingSynchrotron Radiation as Excitation LightSource

International audienceWe review here the photoionization and photoelectron spectroscopy ofthe gas phase nucleic acid bases adenine, thymine, uracil, cytosine, and guanine, aswell as the three base analogues 2-hydroxyisoquinoline, 2-pyridone, andδ-valerolactam in the vacuum ultraviolet (VUV) spectral regime. The chapterfocuses on experimental work performed with VUV synchrotron radiation andrelated ab initio quantum chemical calculations of higher excited states beyondthe ionization energy. After a general part, where experimental and theoreticaltechniques are described in detail, key results are presented by order of growingcomplexity in the spectra of the molecules. Here we concentrate on (1) the accuratedetermination of ionization energies of isolated gas phase NABs and investigationof the vibrational structure of involved ionic states, including their mutual vibroniccouplings, (2) the treatment of tautomerism after photoionization, in competitionwith other intramolecular processes, (3) the study of fragmentation of these molecularsystems at low and high internal energies, and (4) the study of the evolution ofthe covalent character of hydrogen bonding upon substitution, i.e., examination ofelectronic effects (acceptor, donor, etc.)