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P115 Pharmacokinetics (PK) and safety of single and multiple intravenous (IV) infusions of ceftaroline fosamil in healthy Chinese subjects
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Posters / International Journal of Antimicrobial Agents 42S2 (2013) S41–S159
Results: No significant release of LDH was observed from cells incubated with TZD up to 250 mg/L. After cell fractionation, TZD was consistently recovered in the cytosol (final supernates) for both cell types and not detected in fractions enriched in mitochondria. Conclusion: In spite of its higher accumulation in eukaryotic cells compared to LZD, TZD did not cause cell necrosis and was not associated in any stable fashion to mitochondria. The larger cellular accumulation of TZD and lack of specific association with subcellular organelles may therefore be considered as advantageous, as it may ensure the ability of the molecule to diffuse through the various cell compartments and to act against bacteria in different subcellular compartments. We also can rule out general, non-specific cell toxicity in the models used. Reference(s) [1] Lemaire et al., Cellular pharmacokinetics and intracellular activity of torezolid (TR700): studies with human macrophage (THP-1) and endothelial (HUVEC) cell lines. J Antimicrob Chemother. 2009; 64: 1035–43.
P115 Pharmacokinetics (PK) and safety of single and multiple intravenous (IV) infusions of ceftaroline fosamil in healthy Chinese subjects L. Yang1 , H. Li1 , M. Sunzel2 *, P. Xu3 , T. Edeki2 , J. Li2 . 1 Peking University Third Hospital, Beijing, China , 2 AstraZeneca R&D, Wilmington, United States, 3 AstraZeneca China, Shanghai, China E-mail address : [email protected] Introduction: Ceftaroline (CPT), the active metabolite of the prodrug CPT fosamil, shows in vitro bactericidal activity against Grampositive (including MRSA) and common Gram-negative pathogens. We evaluated safety and PK following single and multiple IV CPT fosamil infusions in healthy Chinese subjects. Methods: Healthy males and females (age 18–45 yr, BMI 19–24 kg/m2 ) were sequentially enrolled into two dose cohorts in an open-label, single-centre Phase I study (NCT01458743). On Days 1 and 8, subjects received a single dose of CPT fosamil 600 mg in the morning (Cohort 1, 60 min infusion; Cohort 2, 120 min infusion). Cohort 1 received 600 mg q12 h on Days 3–7 (no study drug on Day 2). Cohort 2 received 600 mg q8 h on Days 2–7. Plasma and urine for PK analysis were collected pre-dose and up to 48 h after the start of infusion. Safety evaluations included adverse events (AEs) monitoring, clinical and laboratory assessments. Results: Of 26 enrolled subjects (Cohort 1, n = 12; Cohort 2, n = 14), 24 completed the Day 8 PK evaluations. CPT fosamil was rapidly converted to CPT in vivo . There was no CPT accumulation from Day 1 to Day 8 in Cohort 1, and limited accumulation in Cohort 2; PK parameters were similar on Day 1 and Day 8 for both cohorts (Table). Approximately 70% of the given dose was recovered as CPT in urine. 22 subjects (11 in each cohort) experienced 1 AE, most frequently drug eruption (n = 10) of mild or moderate intensity (1 reported as severe) and all related to study drug; 4 drug eruptions in Cohort 1 were serious AEs (subjects were kept for observation until resolution); 1 subject in each cohort discontinued due to drug eruption. CPT PK parameters following 600 mg CPT fosamil on Day 1 (single administration) and Day 8 (multiple q12 h [60 min infusion] and q8 h [120 min infusion] administrations) Parameter
Cohort 1 (n = 12)
Cohort 2 (n = 14)
Day 1
Day 8†
Day 1
Day 8‡
AUC (ug*h/mL) Cmax (ug/mL)§ t1/2 (h)
65.4 (17.1) 27.6 (13.4) 2.3 (1.9–2.7)
67.6 (15.9) 27.5 (12.6) 2.3 (1.9–2.7)
66.5 (11.2) 21.0 (10.9) 2.2 (1.8–2.4)
72.2 (8.4) 22.2 (7.8) 2.3 (1.8–2.5)
CL (L/h) Vss (L) CLR
8.1 (14.8) 19.1 (13.4) 5.9 (17.2)
8.0 (14.6) 19.0 (13.9) 5.9 (14.2)
8.0 (10.0) 18.8 (11.6) 5.7 (10.3)
7.9 (7.6) 18.6 (9.6) 5.8 (11.2)
Values shown are geometric mean (%CV) except for t1/2 , which are median (range). † 11 evaluable subjects. ‡ 13 evaluable subjects. § Assessed at steady state on Day 8.
Conclusion: CPT PK were linear and time-independent following single and repeated q12 h and q8 h CPT fosamil dosing. Drug eruption is a known effect of CPT fosamil and cephalosporins. Treatment with
CPT fosamil 600 mg q12 h and q8 h in Chinese subjects was not associated with any new safety concerns. Epidemiology of MRSA, VRE and other Gram-positives P116 Enterococcus faecalis and Enterococcus faecium clinical isolates carrying the vanA gene but susceptible to vancomycin I.K. Bae1 *, H. Lee2 , W. Song3 , S.H. Jeong1 , D. Yong1 , K. Lee1 . Department of Laboratory Medicine, Research Institute of Bacterial Resistance, Yonsei University College of Medicine, 2 Department of Laboratory, Kwandong University College of Medicine, 3 Department of Laboratory, Hallym University College of Medicine, Seoul, Korea, Republic of E-mail address : [email protected] 1
Introduction: Enterococci have emerged in recent years as important nosocomial pathogens. Objectives: This study was performed to characterize Enterococcus faecalis and Enterococcus faecium clinical isolates carrying the vanA gene but susceptible to vancomycin from Korea. Methods: Non-duplicated 141 E. faecalis and 176 E. faecium clinical isolates from blood specimens were collected during January to April 2012 from 31 Korean hospitals. Antimicrobial susceptibilities were tested by disk diffusion method and Etest. PCR experiments were performed to detect the vanA gene. Genetic environments of the vanA gene were investigated by PCR mapping and sequencing the regions surrounding the gene. MLST experiments were performed. Results: E. faecium (19.9%, 35/176) showed higher resistance ratio for vancomycin than E. faecalis (1.4%, 2/141). All vancomycin-resistant Enterococcus spp. clinical isolates carried the vanA gene. Interestingly, the vanA gene was also detected in vancomycin-susceptible isolates of E. faecalis (15.2%, 21/138) and E. faecium (18.4%, 26/141). In these cases, diverse deletion of the genes surrounding the vanA gene was found. E. faecalis clinical isolates carrying the vanA gene but susceptible to vancomycin was identified as ST28 (n = 10), ST179 (n = 3), ST507 (n = 3), ST16 (n = 1), ST64 (n = 1), ST330 (n = 1), ST502 (n = 1), and ST504 (n = 1). E. faecium clinical isolates carrying the vanA gene but susceptible to vancomycin was identified as ST17 (n = 10), ST78 (n = 5), ST230 (n = 3), ST18 (n = 2), ST192 (n = 2), ST252 (n = 1), ST262 (n = 1), ST789 (n = 1), and a novel ST (n = 1). Conclusion: E. faecalis and E. faecium clinical isolates carrying the vanA gene but susceptible to vancomycin were frequently found in our collection. Further studies are needed to understand the clinical importance of these isolates. Reference(s) [1] Gagnon S, Levesque ´ S, Lefebvre B, Bourgault AM, Labbe´ AC, Roger M. vanAcontaining Enterococcus faecium susceptible to vancomycin and teicoplanin because of major nucleotide deletions in Tn1546. J Antimicrob Chemother. 2011 Dec;66(12):2758–62. [2] Johnsen PJ, Østerhus JI, Sletvold H, Sørum M, Kruse H, Nielsen K, Simonsen GS, Sundsfjord A. Persistence of animal and human glycopeptide-resistantenterococci on two Norwegian poultry farms formerly exposed to avoparcin is associated with a widespread plasmid-mediated vanA element within a polyclonal enterococcus faecium population. Appl Environ Microbiol. 2005 Jan;71(1):159–68. [3] Clinical Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing: Twenty-second Informational Supplement M100-S22. Wayne, PA, USA: CLSI, 2012.
P117 Epidemiology of hospital-acquired methicillin-resistant Staphylococcus aureus bloodstream infection at Chiang Mai University Hospital R. Chaiwarith1 *, P. Pacharasupa1. 1 Medicine, Chiang Mai University, Muang, Thailand E-mail address : [email protected] Introduction: The prevalence of methicillin-resistant Staphylococus aureus (MRSA) varies widely depends on geographic region and healthcare setting. The National Antimicrobial Resistance Surveillance Center, Thailand (NARST) reported the prevalence of MRSA ranging from 24% to 28% between 2000 and 2008. The prevalence of MRSA
Posters / International Journal of Antimicrobial Agents 42S2 (2013) S41–S159
Results: No significant release of LDH was observed from cells incubated with TZD up to 250 mg/L. After cell fractionation, TZD was consistently recovered in the cytosol (final supernates) for both cell types and not detected in fractions enriched in mitochondria. Conclusion: In spite of its higher accumulation in eukaryotic cells compared to LZD, TZD did not cause cell necrosis and was not associated in any stable fashion to mitochondria. The larger cellular accumulation of TZD and lack of specific association with subcellular organelles may therefore be considered as advantageous, as it may ensure the ability of the molecule to diffuse through the various cell compartments and to act against bacteria in different subcellular compartments. We also can rule out general, non-specific cell toxicity in the models used. Reference(s) [1] Lemaire et al., Cellular pharmacokinetics and intracellular activity of torezolid (TR700): studies with human macrophage (THP-1) and endothelial (HUVEC) cell lines. J Antimicrob Chemother. 2009; 64: 1035–43.
P115 Pharmacokinetics (PK) and safety of single and multiple intravenous (IV) infusions of ceftaroline fosamil in healthy Chinese subjects L. Yang1 , H. Li1 , M. Sunzel2 *, P. Xu3 , T. Edeki2 , J. Li2 . 1 Peking University Third Hospital, Beijing, China , 2 AstraZeneca R&D, Wilmington, United States, 3 AstraZeneca China, Shanghai, China E-mail address : [email protected] Introduction: Ceftaroline (CPT), the active metabolite of the prodrug CPT fosamil, shows in vitro bactericidal activity against Grampositive (including MRSA) and common Gram-negative pathogens. We evaluated safety and PK following single and multiple IV CPT fosamil infusions in healthy Chinese subjects. Methods: Healthy males and females (age 18–45 yr, BMI 19–24 kg/m2 ) were sequentially enrolled into two dose cohorts in an open-label, single-centre Phase I study (NCT01458743). On Days 1 and 8, subjects received a single dose of CPT fosamil 600 mg in the morning (Cohort 1, 60 min infusion; Cohort 2, 120 min infusion). Cohort 1 received 600 mg q12 h on Days 3–7 (no study drug on Day 2). Cohort 2 received 600 mg q8 h on Days 2–7. Plasma and urine for PK analysis were collected pre-dose and up to 48 h after the start of infusion. Safety evaluations included adverse events (AEs) monitoring, clinical and laboratory assessments. Results: Of 26 enrolled subjects (Cohort 1, n = 12; Cohort 2, n = 14), 24 completed the Day 8 PK evaluations. CPT fosamil was rapidly converted to CPT in vivo . There was no CPT accumulation from Day 1 to Day 8 in Cohort 1, and limited accumulation in Cohort 2; PK parameters were similar on Day 1 and Day 8 for both cohorts (Table). Approximately 70% of the given dose was recovered as CPT in urine. 22 subjects (11 in each cohort) experienced 1 AE, most frequently drug eruption (n = 10) of mild or moderate intensity (1 reported as severe) and all related to study drug; 4 drug eruptions in Cohort 1 were serious AEs (subjects were kept for observation until resolution); 1 subject in each cohort discontinued due to drug eruption. CPT PK parameters following 600 mg CPT fosamil on Day 1 (single administration) and Day 8 (multiple q12 h [60 min infusion] and q8 h [120 min infusion] administrations) Parameter
Cohort 1 (n = 12)
Cohort 2 (n = 14)
Day 1
Day 8†
Day 1
Day 8‡
AUC (ug*h/mL) Cmax (ug/mL)§ t1/2 (h)
65.4 (17.1) 27.6 (13.4) 2.3 (1.9–2.7)
67.6 (15.9) 27.5 (12.6) 2.3 (1.9–2.7)
66.5 (11.2) 21.0 (10.9) 2.2 (1.8–2.4)
72.2 (8.4) 22.2 (7.8) 2.3 (1.8–2.5)
CL (L/h) Vss (L) CLR
8.1 (14.8) 19.1 (13.4) 5.9 (17.2)
8.0 (14.6) 19.0 (13.9) 5.9 (14.2)
8.0 (10.0) 18.8 (11.6) 5.7 (10.3)
7.9 (7.6) 18.6 (9.6) 5.8 (11.2)
Values shown are geometric mean (%CV) except for t1/2 , which are median (range). † 11 evaluable subjects. ‡ 13 evaluable subjects. § Assessed at steady state on Day 8.
Conclusion: CPT PK were linear and time-independent following single and repeated q12 h and q8 h CPT fosamil dosing. Drug eruption is a known effect of CPT fosamil and cephalosporins. Treatment with
CPT fosamil 600 mg q12 h and q8 h in Chinese subjects was not associated with any new safety concerns. Epidemiology of MRSA, VRE and other Gram-positives P116 Enterococcus faecalis and Enterococcus faecium clinical isolates carrying the vanA gene but susceptible to vancomycin I.K. Bae1 *, H. Lee2 , W. Song3 , S.H. Jeong1 , D. Yong1 , K. Lee1 . Department of Laboratory Medicine, Research Institute of Bacterial Resistance, Yonsei University College of Medicine, 2 Department of Laboratory, Kwandong University College of Medicine, 3 Department of Laboratory, Hallym University College of Medicine, Seoul, Korea, Republic of E-mail address : [email protected] 1
Introduction: Enterococci have emerged in recent years as important nosocomial pathogens. Objectives: This study was performed to characterize Enterococcus faecalis and Enterococcus faecium clinical isolates carrying the vanA gene but susceptible to vancomycin from Korea. Methods: Non-duplicated 141 E. faecalis and 176 E. faecium clinical isolates from blood specimens were collected during January to April 2012 from 31 Korean hospitals. Antimicrobial susceptibilities were tested by disk diffusion method and Etest. PCR experiments were performed to detect the vanA gene. Genetic environments of the vanA gene were investigated by PCR mapping and sequencing the regions surrounding the gene. MLST experiments were performed. Results: E. faecium (19.9%, 35/176) showed higher resistance ratio for vancomycin than E. faecalis (1.4%, 2/141). All vancomycin-resistant Enterococcus spp. clinical isolates carried the vanA gene. Interestingly, the vanA gene was also detected in vancomycin-susceptible isolates of E. faecalis (15.2%, 21/138) and E. faecium (18.4%, 26/141). In these cases, diverse deletion of the genes surrounding the vanA gene was found. E. faecalis clinical isolates carrying the vanA gene but susceptible to vancomycin was identified as ST28 (n = 10), ST179 (n = 3), ST507 (n = 3), ST16 (n = 1), ST64 (n = 1), ST330 (n = 1), ST502 (n = 1), and ST504 (n = 1). E. faecium clinical isolates carrying the vanA gene but susceptible to vancomycin was identified as ST17 (n = 10), ST78 (n = 5), ST230 (n = 3), ST18 (n = 2), ST192 (n = 2), ST252 (n = 1), ST262 (n = 1), ST789 (n = 1), and a novel ST (n = 1). Conclusion: E. faecalis and E. faecium clinical isolates carrying the vanA gene but susceptible to vancomycin were frequently found in our collection. Further studies are needed to understand the clinical importance of these isolates. Reference(s) [1] Gagnon S, Levesque ´ S, Lefebvre B, Bourgault AM, Labbe´ AC, Roger M. vanAcontaining Enterococcus faecium susceptible to vancomycin and teicoplanin because of major nucleotide deletions in Tn1546. J Antimicrob Chemother. 2011 Dec;66(12):2758–62. [2] Johnsen PJ, Østerhus JI, Sletvold H, Sørum M, Kruse H, Nielsen K, Simonsen GS, Sundsfjord A. Persistence of animal and human glycopeptide-resistantenterococci on two Norwegian poultry farms formerly exposed to avoparcin is associated with a widespread plasmid-mediated vanA element within a polyclonal enterococcus faecium population. Appl Environ Microbiol. 2005 Jan;71(1):159–68. [3] Clinical Laboratory Standards Institute. Performance Standards for Antimicrobial Susceptibility Testing: Twenty-second Informational Supplement M100-S22. Wayne, PA, USA: CLSI, 2012.
P117 Epidemiology of hospital-acquired methicillin-resistant Staphylococcus aureus bloodstream infection at Chiang Mai University Hospital R. Chaiwarith1 *, P. Pacharasupa1. 1 Medicine, Chiang Mai University, Muang, Thailand E-mail address : [email protected] Introduction: The prevalence of methicillin-resistant Staphylococus aureus (MRSA) varies widely depends on geographic region and healthcare setting. The National Antimicrobial Resistance Surveillance Center, Thailand (NARST) reported the prevalence of MRSA ranging from 24% to 28% between 2000 and 2008. The prevalence of MRSA