MD Conference Express ICAAC 2011 - (Page 20)

n SELECTED UPD ATES I N ANTI BI OTI C RES IS TANC E The mathematical model that he discussed assessed the influence of modifying doses of β-lactam at the population level to estimate the impact on resistance levels and prevalence in colonized individuals. Questions that were considered using this model included the effects of prescription frequency, prescribed dose, and whether defined daily dose (DDD) is a good indicator to predict the evolution of β-lactam resistance to S. pneumoniae. Simulations over a 50-year period of fixed- and variabledose exposure showed a bimodal distribution and that the prevalence of resistance increases with the frequency of exposure. Both findings were consistent with prior epidemiological studies. Dosing outcomes indicated that higher doses may reduce the prevalence of resistance and increase the minimum inhibitory concentration (MIC) of resistant strains. The model also showed that DDD is not an accurate indicator for predicting pneumococcal resistance to β-lacams. “Don’t use DDD to anticipate the future of S. pneumoniae dissemination or to analyze the relationship between antibiotic use and S. pneumoniae resistance,” he said. Which Matters More – Antibiotic Dose or the Bacterium? Patrice Courvalin, MD, Institut Pasteur, Paris, France, discussed the relative importance of antibiotic dose or changes in the bacterial genome in causing antibiotic resistance. Bacteria respond to many changes in their environment by sensing small molecules; yet, competence for genetic transformation is transient. In several bacterial species, it depends on achieving a specialized cellular state [Harvarstein LS et al. Proc Natl Acad Sci 1995]. Harvarstein et al. [Proc Natl Acad Sci 1995] found that competence-stimulating peptide induced competence in pneumococcal cultures in a dose-response fashion to the synthetic peptide, with the highest yield (about 5% of cells transformed) observed at doses of 30 to 1000 ng/mL and a monotonic dose response in the intervening region. Resistance in Acinetobacter spp., particularly Acinetobacter baumannii, provides another example. A. baumannii possesses two intrinsic β-lactamase genes, in addition to weak permeability and efflux systems. Together, they confer a natural reduced susceptibility to antibiotics. Numerous acquired mechanisms of resistance and genetic elements, such as resistance islands, have also been identified [Poirel L et al. IUBMB Life 2011]. Based on these and other findings, Prof. Courvalin concluded that antibiotics promote evolution of resistance (Figure 1). Figure 1. Antibiotics Promote Evolution of Resistance. Antibiotic Stress Competence Transformation Antibiotic Resistance Capsule Exchange Reproduced with permission from P. Courvalin, MD. PK-PD and Resistance William A. Craig, MD, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA, discussed the use of pharmacodynamics/pharmacokinetics (PD/PK) to establish the target that is required to prevent an increase in resistant populations; to identify which PK/PD indices (Cmax, AUC/MIC, T>MIC) or other characteristics best prevent the emergence of resistance; and to determine the magnitude of the PK/PD indices or other characteristics that is required to prevent the development of resistance. With regard to the mutant prevention concentration (MPC) that stops mutant selection at 1010 organisms, he reported that MPC is usually 2- to 16-fold higher than MIC, with selection of resistance higher if drug concentrations persist in the zone between the two concentrations [Blondeau JM et al. Antimicrob Agents Chemother 2001]. He also pointed out the inverted U-shaped distribution of resistance emergence versus dose intensity [Tam VH et al. Antimicrob Agents Chemother 2007]. Dr. Craig discussed aminoglycide dosing to minimize resistance for Enterobacteriaceae and Staphyloccocus aureus (Cmax/MIC >6 [once-daily dosing]) and the need for a Cmax/MIC of 30 with twice-daily dosing of gentamicin to prevent emergence of resistance with P. aeruginosa [Tam VH et al. Antimicrob Agents Chemother 2008]. In addition, he covered PK/PD indices that are associated with in vitro enhancement or suppression of fluoroquinolone resistance, including AUC24/MIC, AUC24/ MPC, and Cmax/MIC, and how doxycycline, combined with moxifloxacin, can reduce emergence of resistant S. aureus [Allen GP, Deshpande LM. Int J Antimicrob Agents 2010]. Dr. Craig concluded that there is a need for more in vivo studies on optimal dosing and combination therapy to effectively prevent resistance. 20 November 2011 www.mdconferencexpress.com http://www.mdconferencexpress.com http://www.mdconferencexpress.com

Table of Contents for the Digital Edition of MD Conference Express ICAAC 2011

MD Conference Express ICAAC 2011
Contents
Infectious Disease Genomics
Emerging Resistance Among Gram-Negative Pathogens
Procalcitonin-Guided Antibiotic Therapy In Patients with Lower Respiratory Tract Infections
Combination Therapy with Flucytosine Improves Survival in AIDS-Related Cryptococcal Meningitis
CXA-201 Effective Against Common ICU Pathogens
Tigecycline Plus Standard Therapy Is More Effective For Treating Infections in Febrile Neutropenic Cancer Patients
Interventions Aimed at Reducing MRSA BSIs Led to Decreased Rates of Nosocomial MSSA BSIs
Is the Effectiveness of aP Vaccine in Pre-Adolescents Insufficient?
TMC435 Effective in the Treatment of HCV Genotype 1 Infection
HIV
Vaccines
Antibiotic Resistance
Drug Discovery
The Conundrum of MDR TB and Combination Therapy
New Drugs to Treat MDR Pathogens
Immunizations in Reproductive Health
Why Can’t Microbes Just Get Along?
The Role of Adjunctive Steroids in the Treatment of Bacterial Meningitis
Human and Animal Viruses Share “One World” and Emerging Zoonotic Infections Continue to Threaten

MD Conference Express ICAAC 2011

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