Scholarly article on topic 'Rates of susceptibility of carbapenems, ceftobiprole, and colistin against clinically important bacteria collected from intensive care units in 2007: Results from the Surveillance of Multicenter Antimicrobial Resistance in Taiwan (SMART)'

Rates of susceptibility of carbapenems, ceftobiprole, and colistin against clinically important bacteria collected from intensive care units in 2007: Results from the Surveillance of Multicenter Antimicrobial Resistance in Taiwan (SMART) Academic research paper on "Biological sciences"

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Abstract of research paper on Biological sciences, author of scientific article — Shio-Shin Jean, Wen-Sen Lee, Kwok-Woon Yu, Chun-Hsing Liao, Chin-Wang Hsu, et al.

Abstract Background Data on susceptibility to ceftobiprole and colistin, and the complete evolutionary trends of minimum inhibitory concentrations (MICs) of important carbapenem agents among important pathogens collected in intensive care units (ICUs) in Taiwan are lacking. Methods We surveyed the MIC distribution patterns of ceftobiprole and colistin and susceptibility profiles of some important pathogens collected from patients hospitalized in intensive care units (ICUs) of major teaching hospitals throughout Taiwan in 2007. We also investigated the rates of nonsusceptibility to powerful carbapenems (imipenem, meropenem) among four important species of Enterobacteriaceae (Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, and Proteus mirabilis) collected during the same period. MIC breakpoints recommended by the Clinical and Laboratory Standards Institute in 2014 were applied. Results Colistin showed excellent in vitro activity (susceptibility rate, 96%) against Acinetobacter baumannii isolates but moderate (73–77% susceptibility rate) activity against isolates of Pseudomonas aeruginosa and E. cloacae. The ceftobiprole MIC90 value was 4 μg/mL for methicillin-resistant Staphylococcus aureus and 16 μg/mL for P. aeruginosa. The phenotype of methicillin resistance did not markedly increase the MIC value of ceftobiprole among S. aureus isolates. Interestingly, the proportion of isolates that displayed nonsusceptibility to imipenem was significantly higher among P. mirabilis isolates than among isolates of the other three Enterobacteriaceae species, regardless of the production of extended-spectrum β-lactamase. Conclusion Continuous monitoring of susceptibility profiles of ICU pathogens to important antibiotics is warranted to provide appropriate antimicrobial regimens against infections in the ICU.

Similar topics of scientific paper in Biological sciences , author of scholarly article — Shio-Shin Jean, Wen-Sen Lee, Kwok-Woon Yu, Chun-Hsing Liao, Chin-Wang Hsu, et al.

Academic research paper on topic "Rates of susceptibility of carbapenems, ceftobiprole, and colistin against clinically important bacteria collected from intensive care units in 2007: Results from the Surveillance of Multicenter Antimicrobial Resistance in Taiwan (SMART)"

Journal of Microbiology, Immunology and Infection (2015) xx, 1-8

ORIGINAL ARTICLE

Rates of susceptibility of carbapenems, ceftobiprole, and Colistin against clinically important bacteria collected from intensive care units in 2007: Results from the Surveillance of Multicenter Antimicrobial Resistance in Taiwan (SMART)

Shio-Shin Jean a, Wen-Sen Lee b, Kwok-Woon Yu c, Chun-Hsing Liao d, Chin-Wang Hsu a, Feng-Yi Chang e, Wen-Chien Ko f, Ray-Jade Chen a, Jiunn-Jong Wu g, Yen-Hsu Chen h, Yao-Shen Chen i, Jien-Wei Liu j, Min-Chi Lu k, Carlos Lam a, Cheng-YiLiu l, Po-Ren Hsueh m *

a Emergency Department, Department of Emergency and Critical Care Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

b Division of Infectious Diseases, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

c Department of Internal Medicine, Pathology and Laboratory Medicine, Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan

d Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei, Taiwan e Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center (NDMC), Taipei, Taiwan

f Department of Internal Medicine, National Cheng-Kung University Hospital, Tainan, Taiwan g School of Medical Technology, National Cheng-Kung University College of Medicine, Tainan, Taiwan h Department of Internal Medicine, Kaohsiung Medical University Hospital, and Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan i Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaoshiung, Taiwan j Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Chang Gung Medical College, Kaohsiung, Taiwan

k Department of Laboratory Medicine and Internal Medicine, Chung Shan Medical and Dental University, Taichung, Taiwan

l Division of Infectious Diseases, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan

* Corresponding author. Departments of Laboratory Medicine and Internal Medicine, National Taiwan University Hospital, 7 Chung-Shan South Road, Taipei 100, Taiwan.

E-mail address: hsporen@ntu.edu.tw (P.-R. Hsueh).

http://dx.doi.org/10.1016/j.jmii.2014.12.008

1684-1182/Copyright © 2015, Taiwan Society of Microbiology. Published by Elsevier Taiwan LLC. All rights reserved.

m Departments of Laboratory Medicine and Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

Received 7 October 2014; received in revised form 29 December 2014; accepted 29 December 2014 Available online ■ ■ ■

KEYWORDS

carbapenem; ceftobiprole; Colistin;

intensive care unit; nonsusceptibility

Abstract Background: Data on susceptibility to ceftobiprole and colistin, and the complete evolutionary trends of minimum inhibitory concentrations (MICs) of important carbapenem agents among important pathogens collected in intensive care units (ICUs) in Taiwan are lacking.

Methods: We surveyed the MIC distribution patterns of ceftobiprole and colistin and susceptibility profiles of some important pathogens collected from patients hospitalized in intensive care units (ICUs) of major teaching hospitals throughout Taiwan in 2007. We also investigated the rates of nonsusceptibility to powerful carbapenems (imipenem, meropenem) among four important species of Enterobacteriaceae (Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, and Proteus mirabilis) collected during the same period. MIC breakpoints recommended by the Clinical and Laboratory Standards Institute in 2014 were applied. Results: Colistin showed excellent in vitro activity (susceptibility rate, 96%) against Acineto-bacter baumannii isolates but moderate (73—77% susceptibility rate) activity against isolates of Pseudomonas aeruginosa and E. cloacae. The ceftobiprole MIC90 value was 4 mg/mL for methicillin-resistant Staphylococcus aureus and 16 mg/mL for P. aeruginosa. The phenotype of methicillin resistance did not markedly increase the MIC value of ceftobiprole among S. aureus isolates. Interestingly, the proportion of isolates that displayed nonsusceptibility to imipenem was significantly higher among P. mirabilis isolates than among isolates of the other three Enterobacteriaceae species, regardless of the production of extended-spectrum ß-lacta-mase.

Conclusion: Continuous monitoring of susceptibility profiles of ICU pathogens to important antibiotics is warranted to provide appropriate antimicrobial regimens against infections in the ICU.

Copyright © 2015, Taiwan Society of Microbiology. Published by Elsevier Taiwan LLC. All rights reserved.

Introduction

The gradual increase in minimum inhibitory concentrations (MICs) of glycopeptides for strains of Staphylococcus aureus (i.e., glycopeptide creep) is a worrisome concern worldwide.1 Infections caused by S. aureus strains with vancomycin MIC levels >2 mg/L are almost always associated with a reduction in clinical efficacy of vancomycin2,3 as well as high morbidity and mortality rates.2,4 Multidrug-resistant (MDR) gram-negative bacteria (GNB) are also an important concern in intensive care units (ICUs) around the world. Because of the coexistence of methicillin-resistant S. aureus (MRSA) and MDR-GNB in most hospitals and nursing homes, physicians often need to prescribe multiple antibiotics for the management of hospital-acquired and health care-associated infections.5

Ceftobiprole, a novel cephalosporin that is effective against MRSA6 and many derepressed AmpC b-lactamase-producing enteric GNB species,7 but not against extended-spectrum b-lactamase (ESBL)-producing Enterobacteriaceae spp.6 has been shown to be as effective as cefepime against GNB, including Pseudomonas aeruginosa

isolates.6 In addition, ceftobiprole exerted less potential of selecting single-step P. aeruginosa mutants of AmpC hy-perproducer than cefepime,8 ceftobiprole has high binding affinity for penicillin-binding protein 2a (PBP2a) and PBP2x, which renders it highly active against penicillin- and ceftriaxone-resistant Streptococcus pneumoniae,6,9 MRSA (regardless of the mecA expression level, and daptomycin susceptibility), and vancomycin-nonsusceptible S. aureus isolates.10 In Taiwan, there is a lack of in vitro susceptibility data regarding ceftobiprole and colistin. The Surveillance of Multicenter Antimicrobial Resistance in Taiwan (SMART), launched in 2000, is designed to longitudinally monitor the in vitro susceptibility profiles of clinical pathogens to important and future promising antibiotic agents, particularly the pathogens isolated from ICUs over time throughout Taiwan. Because the data regarding susceptibility to colistin and ceftobiprole and serial profiles in carbapenem nonsusceptibilities for the important clinical isolates still lacked in our country, we conducted an in vitro survey to evaluate the distributions of MIC values of cef-tobiprole and colistin against S. aureus, important non-fermentative GNB and Enterobacteriaceae isolates, and

compare the trends in MICs of carbapenem agents against isolates of important ESBL-producing and non-ESBL-producing Enterobacteriaceae species using the MIC breakpoints recommended by the Clinical and Laboratory Standards Institute (CLSI) in 2014.11

Methods

Bacterial isolates

From July 1, 2007 through December 31, 2007, a total of 1088 consecutive, nonduplicate isolates of Enter-obacteriaceae, along with 200 isolates of S. aureus, 100 isolates of Acinetobacter baumannii, and 403 isolates of P. aeruginosa (1 isolate per patient) were collected from patients in ICUs at 10 major teaching hospitals (5 in the northern part, 1 in the central part, and 4 in the southern part) throughout Taiwan. The Enterobacteriaceae isolates comprised Escherichia coli (n = 344), Klebsiella pneumoniae (n = 359), Enterobacter cloacae (n = 103), Citrobacter freundii (n = 36), Serratia marcescens (n = 102), Morganella morganii (n = 66), and Proteus mirabilis (n = 78), as reported in our previous study.12 Among the sources of clinical specimens in this study, nearly one-fourth (24.5%) of specimens were collected from sterile sites (16.6% from bloodstream and 7.9% from other sterile sites), whereas 43.1%, 9.4%, and 23% of all specimens were collected from the respiratory tract, wounds, and other nonsterile sites, respectively. In the current survey, the number of clinical isolates submitted by each participating hospital was nearly even. The MIC values of tested antibiotics against these clinical isolates collected in 2007 were determined by the broth microdilution method in accordance with CLSI guidelines. All isolates were stored at -70°C in trypticase soy broth (Difco Laboratories, Detroit, MI, USA) supplemented with 15% glycerol prior to testing. Isolates were then transported to the National Taiwan University Hospital, Taipei, Taiwan for further identification by the Phoenix PMIC/ID-30 identification system (Bec-ton Dickinson Systems, Sparks, MD, USA). E. coli ATCC 25922 and P. aeruginosa ATCC 27853 were used as quality control strains for each run of MIC tests. MIC testing was repeated if the results for ATCC strains were outside the expected range recommended by the CLSI.

Detection of ESBL production, determination of MICs, and nonsusceptibilities to carbapenem agents

For four species of Enterobacteriaceae (E. coli, K. pneumoniae, E. cloacae, and P. mirabilis) collected from ICU settings in 2007, the modified double-disc synergy test, which involves a disc containing cefepime 30 mg, with or without clavulanic acid 10 mg (at a center-to-center distance of 30 mm), instead of a disc containing 4 mg clavulanic acid,13 was applied to detect ESBL production if isolates (E. coli, K. pneumoniae, E. cloacae, and P. mirabilis) had cefotaxime, ceftazidime, or cefepime MIC values >2 mg/mL. The production of ESBL was considered positive if the diameter of the cefepime disc increased by > 5 mm, or the zone diameter expanded by > 50% of the original size, as suggested by M'Zali et al.14 In addition, we

determined the MIC values of carbapenem agents (imipe-nem and meropenem, as well as ertapenem specifically for P. mirabilis isolates, for the reasons described in the Discussion section) against these four species of Enterobacteriaceae isolates obtained as part of the SMART study in 2007 as well as their susceptibility profiles according to MIC breakpoints recommended by the CLSI in 2014.11

Investigations of MICs of colistin and ceftobiprole against important ICU bacteria

We investigated the rates of susceptibility of Enterobacteriaceae members, P. aeruginosa, and A. baumannii to colistin and surveyed the MIC values of ceftobiprole against ICU isolates of S. aureus and P. aeruginosa. Oxacillin MIC values were tested among all S. aureus isolates collected in 2007. All of the antibiotic agents investigated in this study were provided by their respective manufacturers. Ceftobiprole standard powder was provided by Johnson and Johnson Pharmaceutical Research and Development (Raritan, NJ, USA).

Statistical analyses

Categorical variables are presented as percentages and were compared using the Chi-square test. Continuous variables were compared using the Student t test or Mann—Whitney U test, depending on the validity of normality assumption. The coefficient of correlation between the MIC levels of oxacillin and ceftobiprole among the S. aureus isolates (overall vs. MRSA subgroup) was estimated by appropriate correlation methods. All statistical calculations were two-tailed and p < 0.05 was considered to represent statistical significance. All statistical analyses were performed using the statistical package SPSS for Windows (version 17.0; SPSS Inc., Chicago, IL, USA).

Results

Susceptibility of Enterobacteriaceae species, P. aeruginosa, and A. baumannii isolates to colistin

The in vitro data regarding susceptibilities to colistin among isolates of the Enterobacteriaceae members, P. aeruginosa, and A. baumannii obtained from patients hospitalized in ICUs in 2007 are listed in Table 1. Some of the species Enterobacteriaceae family evaluated in this ICU survey exhibited relatively high rates of nonsusceptibility (>25%) to this agent, with the exception of E. coli, K. pneumoniae, and C. freundii. By contrast, the rates of susceptibility to colistin were 76.7% for P. aeruginosa and 96% for A. baumannii isolates collected in ICU settings in 2007.

Comparison of MIC levels of ceftobiprole against isolates of P. aeruginosa and S. aureus

The MIC range, MIC50, and MIC90 values of ceftobiprole against P. aeruginosa isolates obtained from patients in ICUs in 2007 were 0.5—>128, 2 and 16 mg/mL, respectively. Ceftobiprole inhibited 68% of P. aeruginosa isolates at a

Table 1 Susceptibility profile of isolates of Enterobacteriaceae species, Pseudomonas aeruginosa, and Acinetobacter bau-mannii against colistin in intensive care units in Taiwan in 2007

Species (no.) MIC (mg/mL) Susceptibility

MIC range MIC50 MIC90 S(%) I (%) R(%)

Enterobacteriaceae spp. (n = 1088)

Escherichia coli (n = 344) 0.5—>128 1 1 334 (97.1) — 10 (2.9)

Klebsiella pneumoniae (n = 359) 0.5-16 1 1 356 (99.2) — 3 (0.8)

Enterobacter cloacae (n = 103) 0.5—>128 1 >128 75 (72.8) — 28 (27.2)

Citrobacter freundii (n = 36) 1—16 1 8 30 (83.3) — 6 (16.7)

Serratia marcescens (n = 102) 1—>128 >128 >128 9 (8.8) — 93 (91.2)

Morganella morganii (n = 66) 1—>128 >128 >128 2 (3) — 64 (97)

Proteus mirabilis (n = 78) 16—>128 >128 >128 0 (0) — 78 (100)

Nonfermentative gram-negative bacteria (n = 503)

Pseudomonas aeruginosa (n = 403) 2-8 2 4 309 (76.7) 61 (15.1) 33 (8.2)

Acinetobacter baumannii (n = 100) 0.5—>32 1 2 96 (96) — 4 (4)

I = intermediate; MIC = minimum inhibitory concentration; R = resistant; S = susceptible.

concentration of 4 mg/mL, 81.1% of isolates at a concentration of 8 mg/mL, and 91.6% of P. aeruginosa isolates at a concentration of 16 mg/mL (Table 2). We also found that the MIC50 and MIC90 levels for methicillin-susceptible S. aureus isolates (n = 59) were 0.5 mg/mL and 0.5 mg/mL, respectively, and that the MIC50 and MIC90 levels forMRSA isolates (n = 141) were 2 mg/mL and 4 mg/mL, respectively. About 88.7% (125/141) of the MRSA isolates had ceftobiprole MICs of <2 mg/mL, and only one MRSA isolate had a ceftobiprole MIC > 4 mg/mL (64 mg/mL; Table 2). The overall MICs of oxacillin against S. aureus isolates correlated well with the overall MICs of ceftobiprole (Spearman correlation coefficient, r = 0.876, p < 0.001); however, there was a poor correlation between the MICs of those two agents against MRSA isolates (r = 0.263, p = 0.245). In addition, there was a significantly higher proportion of the MRSA isolates with oxacillin MICs >128 mg/mL among MRSA isolates with ceftobiprole MICs ranging from 2 mg/mL to 4 mg/mL than among isolates with ceftobiprole MICs <2 mg/mL (p < 0.001).

Carbapenem susceptibility among four species of Enterobacteriaceae

Comparisons of susceptibilities of non-ESBL and ESBL-producing isolates of four species of Enterobacteriaceae to carbapenem agents (imipenem, meropenem) in 2007 are shown in Table 3. It is worth noting that a few carbapenem-nonsusceptible isolates were found in the ESBL and non-ESBL subgroups of the four species. The absolute number of carbapenem-nonsusceptible isolates in the respective non-ESBL subgroups exceeded that in the ESBL subgroup of

the same species. However, there were no significant differences in the number of carbapenem-nonsusceptible isolates between the two subgroups of all four species. All of the P. mirabilis isolates were susceptible to ertapenem irrespective of ESBL production (MIC < 0.06 mg/mL; data not shown). Furthermore, a rightward shifting trend in imipenem MIC values was noted for P. mirabilis (regardless of ESBL production; Fig. 1A and B) and E. cloacae (ESBL subgroup, Fig. 1A) isolates. This trend was not noted for meropenem MIC levels (data not shown). Although the proportion of imipenem-nonsusceptible P. mirabilis isolates in the ESBL subgroup was significantly higher than that of imipenem-nonsusceptible P. mirabilis isolates in the non-ESBL-producing subgroup (50% vs. 32.8%, p = 0.23), the distribution of imipenem MIC values did not differ significantly between the two P. mirabilis subsets (p = 0.96). By contrast, the distributions of imipenem MICs among P. mirabilis isolates were significantly higher for both non-ESBL- and ESBL-producing subgroups when compared to the respective subgroups of the other three Enter-obacteriaceae species (all p < 0.05). No such trend was found in distribution of meropenem MICs among the four species of the Enterobacteriaceae family.

Discussion

This surveillance study of antimicrobial resistance among important pathogens isolated from patients in the ICU reveals a number of important findings. First, colistin was demonstrated to have excellent in vitro activity against A. baumannii, which contrasted with moderate activity

Table 2 The percentages of isolates of Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus inhibited by different concentrations of ceftobiprole

Species, and % inhibited by the concentration(s) of ceftobiprole 1 mg/mL 2 mg/mL 4 mg/mL 8 mg/mL 16 mg/mL

Pseudomonas aeruginosa (n = 403) MRSA (n = 141) 15.9% 14.9% 56.1% 88.7% 68.0% 99.3% 81.1% 99.3% 91.6% 99.3%

MRSA = methicillin-resistant Staphylococcus aureus.

Table 3 Minimum inhibitory concentration values of two carbapenem agents (imipenem, meropenem) against the species of Enterobacteriaceae family (extended-spectrum ß-lactamase vs. nonextended-spectrum ß-lactamase producing isolates) collected in 2007 and the rates of susceptibility evaluated by the minimum inhibitory concentration breakpoints of the Clinical

and Laboratory Standards Institute, 2C14

Species and antibiotic evaluated MIC (mg/mL) Susceptibility

Range MIC5C MIC9C S(%) I (%) R(%)

Escherichia coli (ESBL) n = 67

IMI C.C6—1 C.25 C.25 67 (1CC) C (C) C (C)

MEM C.C3—C.C6 C.C3 C.C6 67 (1CC) C (C) C (C)

E. coli (non-ESBL), n = 277

IMI C.C6—16 C.12 C.25 273 (9S.6) C (C) 4 (1.4)

MEM C.C3—4 C.C3 C.C3 273 (9S.6) 1 (C.4) 3 (1.1)

Klebsiella pneumoniae (ESBL) n = 75

IMI C.12—>12S C.25 C.5 7C (93.3) 1 (1.3) 4 (5.3)

MEM C.C3—>64 C.C3 C.12 7C (93.3) 1 (1.3) 4 (5.3)

K. pneumoniae (non-ESBL), n = 284

IMI C.C6—S C.25 C.5 273 (96.1) 2 (C.7) 9 (3.2)

MEM C.C3—64 C.C3 C.C6 276 (97.2) 3 (1.1) 5 (1.S)

Enterobacter cloacae (ESBL), n = 19

IMI C.25—S C.25 1 1S (94.7) C (C) 1 (5.3)

MEM C.C3—S C.C6 1 1S (94.7) C (C) 1 (5.3)

E. cloacae (non-ESBL), n = 84

IMI C.12—64 C.5 1 SC (95.2) 1 (1.2) 3 (3.6)

MEM C.C3—S C.C6 C.25 S1 (96.4) 1 (1.2) 2 (2.4)

Proteus mirabilis (ESBL), n = 14

IMI C.25—4 1 4 7 (5C) 3 (21.4) 4 (2S.6)

MEM C.C3—C.25 C.12 C.25 14 (1CC) C (C) C (C)

P. mirabilis (non-ESBL), n = 64

IMI C.C6—S 1 2 43 (67.2) 16 (25) 5 (7.S)

MEM C.C3—4 C.C6 C.25 63 (9S.4) C (C) 1 (1.6)

ESBL, extended-spectrum ß-lactamase; IMI z imipenem; MEM z meropenem; MIC z minimum inhibitory concentration.

against the isolates of P. aeruginosa and some important species of Enterobacteriaceae in 2CC7. Second, MICs of ceftobiprole were very low for P. aeruginosa and MRSA isolates, indicating that ceftobiprole is an attractive choice for empirical management of infections in the ICU setting. Third, we found that imipenem-nonsusceptible P. mirabilis was present in ICUs of Taiwanese hospitals in 2CC7.

Although colistin was administered clinically for only a short period of time in Taiwan prior to 2CC7, the rates of nonsusceptibility among isolates of P. aeruginosa and A. baumannii collected from ICUs in Taiwan in 2CC7 were relatively higher (23.3% and 4%, respectively) than those collected in Turkey during 2C11—2d2.15 Similarly, the rate of susceptibility to colistin (76.7%) among P. aeruginosa isolates obtained in 2CC7 from ICUs in Taiwan was significantly lower than that among P. aeruginosa isolates obtained from ICUs in the United States during 2009-2011 (99.4%).16 A search of the PubMed database revealed a single small case series that documented the outcome of patients with infections due to colistin-resistant enteric GNB. In that study from Saudi Arabia, five of seven critically ill patients with colistin-resistant Enterobacteriaceae species (5 K. pneumoniae, 2 S. marcescens) were successfully treated by various antimicrobial agents.17 More clinical evidence is needed to evaluate the outcome of patients with infection caused by colistin-resistant Enter-obacteriaceae species.

Studies have shown that ceftobiprole has a good phar-macokinetic profile [a peak serum concentration of 35.5 mg/ mL and a high free-drug concentration (plasma protein-bound degree, 16%)18] and a good pharmacodynamic profile (the concentration above MIC is >50% of the total dosing interval forMRSA isolates with vancomycin MICs < 4 mg/mL) when the drug is administered at a dose of 500 mg every 8 hours with a 2-hour intravenous infusion.7 In this survey, the ceftobiprole MIC90 value was 4 mg/mL against MRSA isolates obtained from ICUs in Taiwan, which is twofold higher than that reported in other surveys.6'10'19 It is noteworthy that MRSA isolates with oxacillin MICs > 128 mg/mL largely have ceftobiprole MIC values ranging from 2 mg/mL to 4 mg/mL. This suggests that elevated mecA expression levels in MRSA have little effect on the MICs of ceftobiprole, as reported by Fritsche et al.20 In contrast to ceftaroline fosamil, another anti-MRSA cephalosporin agent with minimal in vitro activity against nonfermentative GNB (especially P. aeruginosa isolates),21 ceftobiprole was verified to have a MIC90 value of 16 mg/mL against ICU isolates of P. aeruginosa, a finding similar to that reported in other sur-veys.19,22 Using Monte Carlo simulation, Lodise et al7 found that a fair probability (62.0%) of target attainment for maximal bactericidal performance (requiring at least 60% of a total dosing interval for a ceftobiprole concentration being above its MIC of the GNB organism) against P. aeruginosa isolates could be achieved when 500 mg is administered

Figure 1. Cumulative minimum inhibitory concentration (MIC) distribution curves for imipenem against (A) ESBL-producing and (B) non-ESBL-producing Enterobacteriaceae species (Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, and Proteus mirabilis) collected from intensive care units in 2001 as part of the SMART study. ESBL z extended-spectrum ß-lactamase.

intravenously every 8 hours with a 2-hour infusion duration.1 Therefore, ceftobiprole is a suitable monotherapy for empirical management of many health care-acquired infections in Taiwan.

Class A carbapenemase [especially, K. pneumoniae car-bapenemase (KPC)] was not detected in the species of Enterobacteriaceae collected in ICU settings in Taiwan before 2011.23—225 Therefore, porin deficiency (impermeability) or efflux pumps in combination with ESBL and/or AmpC enzymes were most likely the major mechanisms conferring carbapenem resistance among Enter-obacteriaceae in Taiwan, as seen in other countries.26-28 In this SMART study conducted in 2001, when KPC (especially KPC-2) did not prevail in ICU settings in Taiwan, we clearly demonstrated that only a low (<5.G%) percentage of important enteric GNB species, with the exception of P. mirabilis, displayed nonsusceptibility to imipenem. In contrast to the data reported in the SMART 2GG5 study,29 we found that the ESBL and non-ESBL subgroups of P. mirabilis

isolates obtained from ICUs were also significantly more nonsusceptible to imipenem than to meropenem and erta-penem (50%/32.8% vs. 0%/1.6% and 0%/0%) based on CLSI 2014 criteria, a finding consistent with that in a recent survey on GNB species responsible for intra-abdominal infections in China.30 Mehtar et al31 reported that clinical P. mirabilis isolates with imipenem MICs > 4 mg/mL predicted treatment failure of imipenem. In this survey, only two (2/ 14, 14.3%) ESBL-producing P. mirabilis isolates and none (0/ 64, 0%) of the non-ESBL-producing P. mirabilis isolates had imipenem MICs > 4 mg/mL. Therefore, the effect of a MIC limit of 4 mg/mL on P. mirabilis analyzed in our ICU study was trivial. In addition, a recent study by Tsai et al,32 who investigated 47 patients with bacteremia caused by ESBL-producing P. mirabilis isolates, reported that none of the three patients with infections due to ESBL-producing P. mirabilis isolates exhibiting imipenem MIC values >2 mg/mL who were treated with imipenem died within 28 days of diagnosis. Further investigations are needed to determine whether the imipenem MIC breakpoint for P. mirabilis isolates should be adjusted. In our study, only three (14.2%) of 21 imipenem-nonsusceptible P. mirabilis isolates were nonsusceptible to cefotaxime and ceftazidime (data not shown). The reason for that finding is probably because most of these imipenem-nonsusceptible P. mirabilis isolates lack imipenem-specific outer membrane proteins,31 have diminished PBP1a expression, or reduced imipenem binding to PBP2.33

There are a few limitations in this study. First, the existence of clonal dissemination could not be completely excluded. Second, we did not characterize the molecular type of SCCmec among MRSA isolates.

In summary, based on 2014 MIC breakpoints recommended by the CLSI, colistin showed only moderate in vitro activity against P. aeruginosa and E. cloacae isolates obtained from ICUs in Taiwan in 2007. Ceftobiprole showed excellent bactericidal activity against MRSA isolates regardless of their oxacillin MIC levels. These two agents exhibited acceptable in vitro activities against P. aerugi-nosa isolates. The clinical importance of high imipenem nonsusceptibility among P. mirabilis isolates based on CLSI 2014 criteria remains debatable. Uninterrupted monitoring of susceptibility profiles of some important ICU pathogens to important antibiotics is still warranted.

Conflicts of interest

None declared.

Acknowledgments

This study was supported by internal funding. Ethical approval was not required.

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